Cancer therapy-induced ovarian failure is a significant public health problem with potentially 1% of population being affected over reproductive life span. Our overall goal is to understand and prevent the damage caused by such treatments. In the previous grant period we made significant discoveries which set the tone for the next grant period. We discovered that gonadotoxic chemotherapeutics result in primordial follicle death primarily by causing double strand (DSB) DNA breaks, and in response to this insult, oocytes mount an ATM- mediated DNA DSB repair response (Aging, 2011). This response may enable some primordial follicles to survive chemotherapy. Furthermore, we found that DNA DSB repair response is critical in the way oocytes mitigate genotoxic insult and aging, and that women who are deficient in DNA DSB repair, specifically BRCA1- mutation carriers, maybe prone to prematurely depleting their ovarian reserve (Science Translational Medicine, 2013). In addition, we showed that S1P, a naturally occurring ceramide death-pathway inhibitor, reduces chemotherapy-induced primordial follicle death in human ovarian xenografts (Human Reproduction 2014). Stemming from these revelations and the DNA DSB repair response being the unifying theme, our specific aims for the renewal application are: 1. To determine if BRCA-mutation carriers are more prone to chemotherapy-induced ovarian follicle loss because of their inherent deficiency of DNA DSB repair; 2. To reveal the mechanisms by which some primordial follicles are able to survive chemotherapy insult; 3. To understand how S1P protects human ovarian primordial follicle pool. To achieve these aims we will utilize clinical studies, single cel real time PCR as well as microarray strategies, in situ hybridization, gene interference, coupled with human ovarian xenografting and laser capture approaches. While the studies are primarily translational and will utilize human material, mouse models will also be used to strengthen the mechanistic work.

Public Health Relevance

Chemotherapy-induced ovarian failure is a major source of health problems. If the mechanisms of chemotherapy-induced oocyte death as well the pathways to repair and prevent such damage are understood, quality of life of cancer survivors can be greatly enhanced.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Taymans, Susan
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New York Medical College
Obstetrics & Gynecology
Schools of Medicine
United States
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Oktay, K; Taylan, E; Rodriguez-Wallberg, K A et al. (2018) Goserelin does not preserve ovarian function against chemotherapy-induced damage. Ann Oncol 29:512-513
Lin, Wayne; Titus, Shiny; Moy, Fred et al. (2017) Ovarian Aging in Women With BRCA Germline Mutations. J Clin Endocrinol Metab 102:3839-3847
Kim, Jayeon; Turan, Volkan; Oktay, Kutluk (2016) Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer. J Clin Endocrinol Metab 101:1364-71
Demeestere, Isabelle; Turan, Volkan; Oktay, Kutluk (2016) Pregnancy Rate and Preservation of Cyclic Ovarian Function With Gonadotropin-Releasing Hormone Agonist Cotreatment During Chemotherapy--Reply. JAMA Oncol 2:546-7
Oktay, Kutluk; Bedoschi, Giuliano; Berkowitz, Karen et al. (2016) Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines. J Pediatr Adolesc Gynecol 29:409-416
Rodriguez-Wallberg, K; Turan, V; Munster, P et al. (2016) Can ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) preserve fertility in cancer patients? Ann Oncol 27:357
Oktay, Kutluk; Bedoschi, Giuliano; Pacheco, Fernanda et al. (2016) First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery. Am J Obstet Gynecol 214:94.e1-9
Oktay, Kutluk; Turan, Volkan (2016) Failure of Ovarian Suppression With Gonadotropin-Releasing Hormone Analogs to Preserve Fertility: An Assessment Based on the Quality of Evidence. JAMA Oncol 2:74-5
Bedoschi, Giuliano; Navarro, Paula Andrea; Oktay, Kutluk (2016) Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol 12:2333-44
Titus, Shiny; Stobezki, Robert; Oktay, Kutluk (2015) Impaired DNA Repair as a Mechanism for Oocyte Aging: Is It Epigenetically Determined? Semin Reprod Med 33:384-8

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