Faculty Bibliography

DNA damage is one of the most common insults that challenge all cells, and more so in resting cell-like oocytes. Increased DNA damage in aged oocyte has been shown to negatively impact the reproductive outcomes. The underlying molecular mechanism is still not completely comprehended, but based on the literature, this decline in the aging oocyte is attributed to impaired DNA repair and epigenetic modifications of these genes with increasing age. In this review, we discuss these molecular alterations and the epigenetic modifications in the DNA double strand break repair gene expressions as a mechanism of oocyte aging.

BACKGROUND:Standard treatments for breast cancer can impair fertility. It is unknown how many U.S. survivors are at risk for infertility. We estimated the population at risk for infertility secondary to treatment among reproductive-aged breast cancer survivors. METHODS:We combined data from three sources: the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results cancer registry data on incident breast cancers diagnosed in women aged 15-44 years between 2004 and 2006; treatment data from NPCR's 2004 Breast and Prostate Cancer Data Quality and Patterns of Care (PoC) study; and data on women's intentions to have children from the 2006-2010 National Survey of Family Growth (NSFG). RESULTS:In the cancer registry data, an average of 20,308 women with breast cancer aged <45 years were diagnosed annually. Based on estimates from PoC data, almost all of these survivors (97%, 19,416 women) were hormone receptor positive or received chemotherapy and would be at risk for infertility. These women need information about the impact of treatments on fertility. Estimates based on NSFG data suggest approximately half of these survivors (9,569 women) might want children and could benefit from fertility counseling and fertility preservation. CONCLUSION/CONCLUSIONS:Nearly all young breast cancer survivors in the U.S. are at risk for infertility. Physicians should discuss the potential impact of treatment on fertility. A smaller but sizeable number of at-risk survivors may be interested in having children. Given the magnitude of potential infertility and its quality-of-life implications, these survivors should have access to and potential coverage for fertility services.

The majority of children, adolescents, and young adults diagnosed with cancer today will become long-term survivors. The threat to fertility that cancer treatments pose to young patients cannot be prevented in many cases, and thus research into methods for fertility preservation is developing, aiming at offering cancer patients the ability to have biologically related children in the future. This paper discusses the current status of fertility preservation methods when infertility risks are related to surgical oncologic treatments, radiation therapy, or chemotherapy. Several scientific groups and societies have developed consensus documents and guidelines for fertility preservation. Decisions about fertility and imminent potentially gonadotoxic therapies must be made rapidly. Timely and complete information on the impact of cancer treatment on fertility and fertility preservation options should be presented to all patients when a cancer treatment is planned.

STUDY QUESTION/OBJECTIVE:Can Sphingosine-1-phosphate (S1P), a ceramide-induced death pathway inhibitor, prevent cyclophosphamide (Cy) or doxorubicin (Doxo) induced apoptotic follicle death in human ovarian xenografts? SUMMARY ANSWER/CONCLUSIONS:S1P can block human apoptotic follicle death induced by both drugs, which have differing mechanisms of cytotoxicity. WHAT IS KNOWN ALREADY/BACKGROUND:S1P has been shown to decrease the impact of chemotherapy and radiation on germinal vesicle oocytes in animal studies but no human translational data exist. STUDY DESIGN, SIZE, DURATION/METHODS:Experimental human ovarian xenografting to test the in vivo protective effect of S1P on primordial follicle survival in the chemotherapy setting. The data were validated by assessing the same protective effect in the ovaries of xenografted mice in parallel. PARTICIPANTS/MATERIALS, SETTING, METHODS/METHODS:Xenografted mice were treated with Cy (75 mg/kg), Cy+S1P (200 μM), Doxo (10 mg/kg), Doxo+S1P or vehicle only (Control). S1P was administered via continuous infusion using a mini-osmotic pump beginning 24 h prior to and ending 72 h post-chemotherapy. Grafts were then recovered and stained with anti-caspase 3 antibody for the detection of apoptosis in primordial follicles. The percentage of apoptotic to total primordial follicles was calculated in each group. MAIN RESULTS AND THE ROLE OF CHANCE/RESULTS:Both Cy and Doxo resulted in a significant increase in apoptotic follicle death in human ovarian xenografts compared with controls (62.0 ± 3.9% versus 25.7 ± 7.4%, P < 0.01 and 76.7 ± 7.4% versus 25.7 ± 7.4%, P < 0.01, respectively). This chemotherapy-induced apoptotic death was reduced both in the Cy+S1P (32.7 ± 4.4%, P < 0.01) and the Doxo+S1P group (27.1 ± 7.6%, P < 0.01) compared with Cy and Doxo groups, respectively. In the Doxo+S1P and Cy+S1P groups, the percentages of apoptotic follicles were similar to those of vehicle-treated controls (P > 0.05). The findings from the ovaries of the severe combined immunodeficient mice mirrored the findings with human tissue. LIMITATIONS, REASONS FOR CAUTION/CONCLUSIONS:The functionality of the rescued human ovarian follicles needs to be evaluated in future studies though the studies in rodents showed that rescued oocytes can result in healthy offspring. In addition, the impact of S1P on cancer cells should be further studied. WIDER IMPLICATIONS OF THE FINDINGS/CONCLUSIONS:S1P and its future analogs hold promise for preserving fertility by pharmacological means for patients undergoing chemotherapy. STUDY FUNDING/COMPETING INTEREST(S)/BACKGROUND:This research is supported by NIH's NICHD and NCI (5R01HD053112-06 and 5R21HD061259-02) and the Flemish Foundation for Scientific Research (FWO-Vlaanderen, grant number FWO G0.065.11N10). The authors have no conflicts of interest to disclose.

INTRODUCTION/BACKGROUND:Earlier diagnosis and novel chemotherapy strategies have resulted in a considerable improvement in cancer survival, but the quality of that survival is influenced by late effects of chemotherapy. Premature ovarian failure is a common consequence of chemotherapy in reproductive-aged women, and, as a result, fertility issues and sexual dysfunction occur frequently in women who have undergone chemotherapy. AREAS COVERED/METHODS:This article reviews what is known about the effects of chemotherapy on fertility and sexuality. We also discuss risk factors for premature ovarian failure, fertility preservation options in patients willing to have a child after treatment, and sexual changes associated with estrogen withdrawal and psychological factors. EXPERT OPINION/CONCLUSIONS:Chemotherapy-induced ovarian failure in young women is associated with poorer quality of life, decreased sexual functioning, psychosocial distress related to fertility concerns, and infertility. Fertility preservation options should be considered in women at risk of premature ovarian failure caused by chemotherapy. Sexual dysfunction associated with estrogen withdrawal and psychological stress is common in cancer survivors. Women who suffer from sexual dysfunction may benefit from brief counseling and targeted intervention.

PURPOSE: To analyze the cycle outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS), when oocyte maturation was triggered by gonadotropin-releasing hormone agonist (GnRHa) versus human chorionic gonadotropin (hCG) in breast cancer patients undergoing fertility preservation. METHODS: One hundred twenty-nine women aged