Faculty Bibliography

Cancer is a major public health problem around the world. Currently, about 5% of women diagnosed with cancer are of reproductive age. These young survivors may face compromised fertility. The effects of chemotherapeutic agents on ovarian reserve and its clinical consequences are generally inferred from a variety of surrogate markers of ovarian reserve, all aiming to provide prognostic information on fertility or the likelihood of success of infertility treatment. Until recently, the mechanisms that are responsible for chemotherapy-induced ovarian damage were not fully elucidated. The understanding of these mechanisms may lead to targeted treatments to preserve fertility. In this manuscript, we will review the current knowledge on the mechanism of ovarian damage and clinical impact of chemotherapy agents on fertility.

In this article we review the existing fertility preservation options for women diagnosed with Turner syndrome and provide practical guidelines for the practitioner. Turner syndrome is the most common sex chromosome abnormality in women, occurring in approximately 1 in 2500 live births. Women with Turner syndrome are at extremely high risk for primary ovarian insufficiency and infertility. Although approximately 70%-80% have no spontaneous pubertal development and 90% experience primary amenorrhea, the remainder might possess a small residual of ovarian follicles at birth or early childhood. The present challenge is to identify these women as early in life as is possible, to allow them to benefit from a variety of existing fertility preservation options. To maximize the benefits of fertility preservation, all women with Turner syndrome should be evaluated by an expert as soon as possible in childhood because the vast majority will have their ovarian reserve depleted before adulthood. Cryopreservation of mature oocytes and embryos is a proven fertility preservation approach, and cryopreservation of ovarian tissue is a promising technique with a growing number of live births, but remains investigational. Oocyte cryopreservation has been performed in children with Turner syndrome as young as 13 years of age and ovarian tissue cryopreservation in affected prepubertal children. However, current efficacy of these approaches is unknown in this cohort. For those who have already lost their ovarian reserve, oocyte or embryo donation and adoption are strategies that allow fulfillment of the desire for parenting. For those with Turner syndrome-related cardiac contraindications to pregnancy, use of gestational surrogacy allows the possibility of biological parenting using their own oocytes. Alternatively, gestational surrogacy can serve to carry pregnancy resulting from the use of donor oocytes or embryos, if needed.

CONTEXT AND OBJECTIVE:There has been increased attention to the issue of fertility preservation (FP). We aimed to investigate the long-term safety of FP via controlled ovarian stimulation with letrozole supplementation (COSTLES) prior to breast cancer treatment. DESIGN, SETTING, AND PARTICIPANTS:This is a prospective, nonrandomized, controlled study conducted between the years 2002 and 2014. A total of 337 women diagnosed with stage 3 or less invasive breast cancer were enrolled during a FP consultation before chemotherapy. Of those, 120 elected to undergo COSTLES for FP prior to chemotherapy (FP group). The remaining 217 patients did not undergo any FP procedure and served as the controls. MAIN OUTCOME MEASURE:The primary end point was cancer recurrence defined as the detection of locoregional tumor (chest wall, regional nodal disease), distant metastases, or contralateral invasive breast cancer. RESULTS:The baseline characteristics at enrollment were similar between the FP and control groups except for the less frequent lymph node involvement (P = .02) in the former. The mean follow-up after diagnosis was 5.0 years in the FP group and 6.9 years in the control group. In the FP group, the hazard ratio for recurrence after ovarian stimulation was 0.77 (95% confidence interval 0.28–2.13), and the survival was not compromised compared with controls (P = .61). Neither BRCA gene mutation status (P = .57) nor undergoing FP before or after breast surgery (P = .44) affected survival outcomes in the FP group. Likewise, none of the tumor characteristics including the estrogen receptor status affected the survival rates after the COSTLES. CONCLUSIONS:COSTLES is unlikely to cause a substantially increased recurrence risk in breast cancer during the 5 years after diagnosis.

BACKGROUND:Ovarian tissue cryopreservation is an experimental fertility preservation method and the transplantation techniques are still evolving. OBJECTIVE:We attempted to improve the technique with the utility of a human decellularized extracellular tissue matrix (ECTM) scaffold, robot-assisted minimally invasive surgery, and perioperative pharmacological support. STUDY DESIGN/METHODS:We prospectively studied 2 subjects with hemophagocytic lymphohistiocytosis (patient A) and non-Hodgkin lymphoma (patient B) who underwent ovarian tissue cryopreservation at the age of 23 years, before receiving preconditioning chemotherapy for hematopoietic stem cell transplantation. Both experienced ovarian failure postchemotherapy and we transplanted ovarian cortical tissues to the contralateral menopausal ovary 7 and 12 years later, using a human ECTM scaffold and robotic assistance. The ECTM scaffold tissue compatibility was shown in preclinical studies. Patients also received estrogen supplementation and baby aspirin preoperatively to aid in the revascularization process. RESULTS:Ovarian follicle development was observed approximately 10 (patient A) and 8 (patient B) weeks after ovarian tissue transplantation. Following 8 and 7 cycles of in vitro fertilization, 9 and 10 day-3 embryos were cryopreserved (patients A and B, respectively). While the baseline follicle-stimulating hormone (range 3.6-15.4 mIU/mL) levels near normalized by 7 months and remained steady postovarian transplantation in patient A, patient B showed improved but elevated follicle-stimulating hormone levels throughout (range 21-31 mIU/mL). Highest follicle yield was achieved 14 (8 follicles; patient A) and 11 (6 follicles; patient B) months postintervention. Patient A experienced a chemical pregnancy after the third frozen embryo transfer attempt. She then conceived following her first fresh in vitro fertilization embryo transfer and the pregnancy is currently ongoing. Patient B conceived after the first frozen embryo transfer attempt and delivered a healthy girl at term. CONCLUSION/CONCLUSIONS:We report the first pregnancies after the minimally invasive transplantation of previously cryopreserved ovarian tissue with an ECTM scaffold. This approach seems to be associated with steady ovarian function after a follow-up of up to 2 years.

BACKGROUND:Mitochondrial dysfunction has been suggested as a major cause of age-induced decline in oocyte quality. In the past, donor oocyte cytoplasmic transfer showed some success but was abandoned due to the concerns with heteroplasmy. Recent studies indicated presence of oogonial precursor cells (OPCs) in the human ovary, which could be an autologous source of "healthy mitochondria." We sought to investigate the clinical efficacy of OPC-derived autologous mitochondrial injection (AMI) to improve oocyte quality in women with multiple in vitro fertilization (IVF) failures. METHODS:The OPCs were isolated from laparoscopically obtained ovarian cortical pieces by cell sorting using a monoclonal anti-vasa homolog (anti-DDX) antibody. They were then disrupted and mitochondria were isolated. Reconstituted mitochondria were injected into each oocyte during intracytoplasmic sperm injection. Paired comparisons were made between the first failed cycles and the post-AMI cycles. RESULTS:Of the 15 women undergoing ovarian stimulation, 2 were canceled and 3 decided to pool oocytes for later AMI. In remaining 10 (mean age 34.7 ± 4.1), AMI significantly improved fertilization rates (49.7 ± 31.3 vs 78.3 ± 18.9; P = .03) with a trend for better embryo grades (2.3 ± 0.3 vs 3.1 ± 0.7; P = .08). Four of 10 women conceived after single frozen embryo transfer and 3 after confirmation of diploidy via array comparative genomic hybridization (aCGH) (clinical pregnancy/embryo transfer = 4/10). CONCLUSION/CONCLUSIONS:These data show encouraging results for AMI in comparison to previous failed IVF cycles.

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.

Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.