Mary B. Zelinski
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.With collaborators in the Oncofertility Consortium (http://oncofertility.northwestern.edu/) , we are 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 cryopreservation (vitrification) methods for preserving ovarian tissue for subsequent transplantation or 3-dimensional follicle culture. Our ultimate goal is to demonstrate that each method will yield oocytes that can fertilize and lead to live offspring, thus providing 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 fertilitzation; 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.
Peluffo M, Stanley J, Braeuer N, Rotgeri A, Fritzemeier K-H, Fuhrmann U, Buchmann B, Adevai T, Murphy MJ, Zelinski MB, Lindenthal B. Hennebold J, Stouffer RL. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques. Hum Reprod, accepted for publication, 2014. Finalist for Scientific Program Prize Paper, 68th Annual Meeting of the American Society for Reproductive Medicine, 2012.
Xu J, Xu M, Bernuci MP, Fisher TE, Shea LD, Woodruff TK, Zelinski MB, Stouffer RL. Primate follicular development and oocyte maturation in vitro. Adv Exp Med Biol. 2013;761:43-67. PMID: 24097381. PMCID in progress.
Telfer EE,Zelinski MB. Ovarian follicle cutlure: advances and challenges for human and nonhuman primates. Fertil Steril 99:1523-33, 2013. PMC3712659
Waimey K, Duncan FE, Su HI, Smith K, Wallach H, Jona K, Coutifaris C, Gracia CR, Shea LD, Brannigan RE, Chang RJ, Zelinski MB, Stouffer RL, Taylor RL, Woodruff TK. Future directions in oncofertility and fertility preservation: a report from the 2011 Oncofertility Consortium Conference. J Adolescent Young Adult Oncol, 2:25-30, 2013. PMC3604786
Ting AY, Yeoman RR, Campos JR, Lawson MS, Mullen SF, Fahy GM, Zelinski MB. Morphological and functional preservation of preantral follicles after vitrification of macaque ovarian tissue in a closed system. Hum Reprod, 28:1267-79, 2013. Finalist for Scientific Program Prize Paper, 68th Annual Meeting of the American Society for Reproductive Medicine, 2012. PMC3627338 [Available on 2014/5/1]
Peluffo M, Hennebold J, Stouffer RL, Zelinski MB. Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys. J Asst Reprod Genetics, 30:353-359, 2013. PMC3607688
Xu J, Lawson MS, Yeoman RR, Moslkness TA, Ting AY, Zelinski MB, Stouffer RL. Fibrin promotes development and function of macaque primary follicles during encapsulated 3-dimensional culture. Hum Reprod, 28:2187-2200, 2013. PMID: 23608357 PMCID in progress
Ting AY, Yeoman RR, Lawson MS and Zelinski MB. Synthetic polymers improve vitrification outcomes of macaque ovarian tissue as assessed by histological integrity and the in vitro development of secondary follicles. Cryobiology 65:1-11, 2012. PMC3572200
Ting AY, Yeoman RR, Lawson MS, Zelinski MB. In vitro development of secondary follicles from cryopreserved rhesus macaque ovarian tissue after slow-rate freeze or vitrification. Hum Reprod, 26:2461-2472, 2011. PMC3157627
Zelinski, MB, Murphy M, Lawson M, Pau F, Toscano N, Jacob D, Fanton J, Tilly JL. Intraovarian delivery of a spingosine-1 phosphate (S1O) agonist, FTY720, prior to ovarian X-irradiation yields fertilization, embryonic development and pregnancy in rhesus monkeys. Fertil Steril, 15:1440-1445.e1-7, 2011. Scientific Program Prize paper, 64th Annual Meeting of the American Society for Reproductive Medicine, 2008. PMC3033448
Xu J, Lawson MS, Yeoman RR, Zelinski MB, Stouffer RL. Secondary follicle growth and oocyte maturation during encapsulated three-dimensional culture in rhesus monkeys: effects of gonadotropins, oxygen, and fetuin. Hum Reprod, 26:1061-1072, 2011. PMC3079470
Xu J, Bernuci MP, Lawson MS, Yeoman RR, Fisher TE, Zelinski MB, and Stouffer RL. Survival, growth, and maturation of secondary follicles from prepubertal, young and older adult, rhesus monkeys during encapsulated three-dimensional (3D) culture: effects of gonadotropins and insulin. Reproduction, 140:685-97, 2010. PMC3351200
Smitz J, Dolmans MM, Donnez J, Fortune JE, Hovatta O, Jewgenow K, Picton HM, Plancha C, Shea LD, Stouffer RL, Telfer EE, Woodruff TK, Zelinski MB. Current achievements and future research directions in ovarian tissue culture, in vitro follicle development and transplantation: implications for fertility preservation. Hum Reprod,16:395-414, 2010. PMC2880913
Peluffo M, Stouffer RL, Hennebold JD, Zelinski MB. Cumulus oocyte complexes from small antral follicles during the early follicular phase of spontaneous cycles in rhesus monkeys can expand and yield oocytes capable of maturation in vitro. Biol Reprod. 83:525-32, 2010. PMC2957158
Shiying Jin S, Lei L, Shea LD, Zelinski MB, Stouffer RL, Woodruff TK. Markers of growth and development in primate primordial follicles are preserved after slow cryopreservation. Fertil Steril, 93:2627-32, 2010. PMC2873131
Jensen JT, Stouffer RL, Stanley JE, Zelinski MB. Evaluation of the phosphodiesterase 3 inhibitor ORG9935 as a contraceptive in female macaques: initial trials. Contraception 81:165-171, 2010. PMC2813210.
Jensen JT, Vance J, Zelinski MB, Fanton JW, Stouffer RL. The phosphodiestrase inhibitor ORG 9935 inhibits oocyte maturation in the naturally-selected dominant follicle in rhesus monkeys. Contraception, 77:303-307, 2008. PMC2505347
Lee DM, Yeoman RR, Battaglia DE, Stouffer RL, Zelinski-Wooten MB, Fanton JW, Wolf DP. Live birth after ovarian tissue transplant. Nature, 428:137-138, 2004. PMID: 15014485