Chemotherapy-induced ovarian failure is a growing public health problem with a major impact on quality of life. If individual toxicity of chemotherapy agents is known, patients can be counseled about the likelihood of ovarian damage and the need for fertility preservation. Moreover, if pharmacological ovarian protection strategies are developed, there will be no need for surgical interventions to preserve fertility, thus reducing concomitant risks and costs. The long term goal of this project is to improve our understanding of the risks of chemotherapy-induced ovarian failure by developing more accurate ovarian reserve assessment strategies and xenografting models, in addition to testing the effectiveness of pharmacological approaches to prevent chemotherapy induced damage to ovarian reserve in a xenograft model. The proposal focuses on breast cancer since it is the most common malignancy in young women.
The specific aims are: (1) To determine the impact of commonly used breast cancer chemotherapy regimens on ovarian reserve using existing and emerging markers of the follicle population. Antral follicle counts, Inhibin-B, anti-mullerian hormone, and FSH/estradiol measurements will be obtained pre-and post-chemotherapy with a 2.0-4.5 year follow-up. (2) To measure the degree and determine the mechanism of damage caused by chemotherapeutics in human ovary. Immunodeficient mice with human ovarian tissue xenografts will be treated with commonly used and emerging agents, or the vehicle;changes in follicle density, as well as the extent of apoptotic follicular death as quantified by pre-cleaved caspase-3 expression will be used to measure the impact. An alternative mechanism of follicular loss by microvascular damage will also be investigated by quantitative vascular assessment methods and intra-vital dye injection. Moreover, we will investigate whether double strand DMA breaks are induced in the surviving primordial follicles by the analysis of ATM pathway proteins involved in DMA repair. (3) To determine whether a cell death inhibitor S1P protects against chemotherapy-induced damage to the primordial follicle pool, and ascertain whether the mechanism involves direct effects on primordial follicles via S1P receptors, or protection of ovarian microvasculature.
These aims will be studied in short-and long-term xenograft models where not only the primordial follicle survival but the potential of S1P- protected primordial follicles to develop into antral stages and produce competent oocytes will be tested.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD053112-06
Application #
8122307
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2007-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
6
Fiscal Year
2011
Total Cost
$283,225
Indirect Cost
Name
New York Medical College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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
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
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
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
Bedoschi, Giuliano; Navarro, Paula Andrea; Oktay, Kutluk (2016) Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol 12:2333-44
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 29:409-16
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
Oktay, Kutluk; Turan, Volkan; Bedoschi, Giuliano et al. (2015) Fertility Preservation Success Subsequent to Concurrent Aromatase Inhibitor Treatment and Ovarian Stimulation in Women With Breast Cancer. J Clin Oncol 33:2424-9
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
Oktay, Kutluk; Turan, Volkan; Titus, Shiny et al. (2015) BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging. Biol Reprod 93:67

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