Faculty Bibliography

BACKGROUND:Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated (ATM)-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and ATM-mediated DNA DSB repair in ovarian aging. OBJECTIVE AND RATIONALE:Although there are several competing or complementary theories, given the growing evidence tying BRCA function and ATM-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. SEARCH METHODS:We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. OUTCOMES:Laboratory studies provided robust and reproducible evidence that BRCA1 function and ATM-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other ATM-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related ATM-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. WIDER IMPLICATIONS:The existing data suggest that the BRCA-related ATM-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.

An increasing number of women in modern societies are delaying childbearing beyond the age of 35, and gynecologic cancers affect a significant proportion of reproductive age women who wish to preserve fertility for a future chance of childbearing. As a result, providing treatment options for fertility preservation in women with gynecologic cancer has become a crucial component of cancer survivorship care. In this review article, we discussed the current knowledge on fertility-sparing surgical approaches, as well as assisted reproductive technologies that can be utilized to preserve reproductive potential in women with cervical, endometrial, and ovarian cancer. A brief section on fertility preservation in pediatric gynecologic malignancies is also provided.

CONTEXT/BACKGROUND:Powerful demographic transitions towards aging of human populations, older age at first childbirth, and lower birth-rates will profoundly influence the health, vitality, and economies of human societies, and deserve greater attention in health policy and research. EVIDENCE ACQUISITION/METHODS:Information on birth-rates, fertility rates, and outcomes of assisted reproductive technologies were obtained from databases of government agencies (census data, Centers for Disease Control). EVIDENCE SYNTHESIS/RESULTS:Fecundity declines with advancing age, especially in women >35 and in men >50. Advanced parental age adversely affects pregnancy outcomes for the mother and the offspring, and increases the offspring's risk of chromosomal disorders, neurodegenerative diseases and birth defects. Because of increased life expectancy, today, men and women can expect to spend a major portion of their life during a period of reproductive senescence; diseases associated with reproductive senescence will influence the health and wellbeing of middle-aged and older adults. Inversion of the population age pyramid would affect healthcare costs, retirement age, generational distribution of wealth, and the vitality of human societies.Several actions can be taken to mitigate the societal consequences of these trends. An educational campaign to inform young people about the trade-offs associated with postponement of childbirth will enable them to make informed choices. Some repositioning of research agenda and healthcare policy is needed to address the public health threat posed by reproductive aging. CONCLUSION/CONCLUSIONS:The societal consequences of low fertility rates and delayed parenthood on nation's health, vitality, and economic growth should be considered in crafting research, health and economic policy.

For female patients facing fertility-impairing treatment for select cancers and other medical conditions, fertility-preserving surgeries have evolved to meet the needs of those who desire fertility preservation. Over the last 70 years, advances in surgical options for fertility preservation have vastly increased in scope and availability. Major breakthroughs in fertility-preservation surgeries include the development of ovarian transposition procedures as well as uterine fixation; both procedures move these vital reproductive organs away from radiation fields to help protect and preserve future fertility. Since the first transplantation of thawed cryopreserved ovarian tissue 20 years ago, there have been major advances in techniques to optimize outcomes. Additionally, surgeries specific for gynecologic malignancies, including radical trachelectomy, have allowed for the preservation of vital reproductive organs. This juncture between innovation and technology resulting in fertility-sparing surgical options for cancer patients illustrates both surgical creativity and continued commitment to develop new techniques, while improving those already in practice. This review explores current advancements in fertility-preserving reproductive surgery, highlighting significant historical landmarks and recent major developments.

OBJECTIVE:To demonstrate the technical advances since the time we reported the first successful case in 2000 and our modern approach to autologous transplantation of frozen-thawed human ovarian tissue. DESIGN:A step-by-step video demonstration of three surgical approaches was created by editing the surgical footage obtained during ovarian transplantation procedures. SETTING:Academic. PATIENT(S):Three patients who previously underwent ovarian tissue harvesting and cryopreservation before gonadotoxic cancer treatments or radical cancer surgery are presented. INTERVENTION(S):The illustrated techniques include robot-assisted orthotopic (technique 1) and heterotopic (technique 2) approaches using the da Vinci Xi (Intuitive Surgical) robotic system and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp.) as a tissue scaffold, as well as a percutaneous autotransplantation approach (technique 3). MAIN OUTCOME MEASURE(S):production and follicle development. RESULT(S):production, follicle growth by 10-14 weeks after transplantation, and later embryo development. CONCLUSION(S):Since our first report of successful restoration of ovarian function after orthotopic transplantation of frozen-banked ovarian tissue in 2000 (1), followed by our first reports of subcutaneous heterotopic transplantation techniques (2, 3), ovarian tissue cryopreservation followed by subsequent transplantation has become a promising fertility preservation option for young women with cancer who do not have sufficient time to undergo oocyte or embryo cryopreservation and for prepubertal girls (4, 5). The same approach also has the advantage of restoring ovarian endocrine function and fertility without a need for assisted reproduction (6, 7). In the very first successful procedure that we reported in 2000, we used conventional laparoscopy, and the tissues were reconstructed and mounted on a polycellulose scaffold (Surgicel) (1, 7). Since then, we have made significant modifications in our surgical approach with potential improvements in outcomes. Here we illustrate three main techniques of ovarian tissue transplantation resulting in the restoration of ovarian function in all cases. In the first two cases, we illustrated the robot-assisted orthotopic and heterotopic approaches using Alloderm. Robotic ovarian transplantation may increase precision, provide more delicate graft handling, and reduce the time from tissue thawing to transplantation (6, 8). Alloderm is regenerated de-epithelized human cadaver skin, which consists of several extracellular matrix components. It has been safely used in the surgery and dentistry fields for enhancing tissue regeneration and vascularization (9, 10). Furthermore, our earlier laboratory work indicated the critical role of extracellular matrix in primordial follicle growth initiation and preantral follicle growth (11, 12). Prior to our use of Alloderm as part of ovarian transplant procedures, we tested it in human ovarian xenograft models and found Alloderm to incorporate well with ovarian tissue (8). Only after that test did we adopt it for use in ovarian transplants. The utility of the extracellular tissue matrix may thus enhance our ovarian autotransplantation techniques by facilitating ovarian reconstruction and potentially improving neovascularization. In fact, we have seen improved follicle growth and response to ovarian stimulation with the use of Alloderm in our first cases (8). We use heterotopic ovarian transplantation when the pelvis is not suitable for autotransplantation due to past radiation or scarring or when there are other medical contraindications for transplantation in the pelvis. The third technique we illustrated was percutaneous heterotopic ovarian autotransplantation. This is a simple approach that can be used in surgically high-risk patients, as it is done with local anesthesia or IV sedation and without entering abdominal cavity. Additionally, same approach can be utilized when there is heightened concern that the ovarian tissue may harbor a disease that can recur, requiring close surveillance and easier removal of the ovarian graft. While ovarian endocrine function and follicle growth are restored with efficiency using the percutaneous ovarian transplants, our initial experience suggests that oocyte quality may be impaired in SC locations (2, 3, 13). Hence that technique may be more suitable when the only purpose is restoration of ovarian endocrine function. However, we have encountered recurrent live births from spontaneous conceptions following SC ovarian transplants, prompting the question of whether the grafted tissue can augment the function of in situ menopausal ovary (13, 14). While ovarian cryopreservation and transplantation may no longer be considered experimental, there are many exciting questions remaining to be answered on the full potential of this procedure.

Cancer is the second leading cause of death in the USA and is considered a public health issue worldwide. Early diagnosis and advancement of treatment modalities contributed to declining mortality rates. Consequently, survival rates increased, leading to a greater interest in maintaining the quality of life after cancer treatment. Overall survival and disease-free survival rates are improved with the use of adjuvant chemotherapy. However, chemotherapy treatment might cause short and long-term side effects for cancer survivors. A special concern of young women diagnosed with cancer is their reproductive potential after chemotherapy. Chemotherapy drugs act by distinct mechanisms in the ovaries. DNA damage of primordial follicle oocytes, leading to chemotherapy-induced apoptosis, was recognized as the principal mechanism responsible for the irreversible decline of the ovarian reserve. The oocyte first attempts to repair DNA damage via the DNA damage repair pathway mediated by ataxia-telangiectasia mutated. Elimination through apoptosis occurs in cells in which DNA damage could not be repaired. In this review, the clinical impact and the major mechanisms of ovarian damage from chemotherapy treatment will be briefly described.

OBJECTIVE:To evaluate the impact of cancer diagnosis on response to ovarian stimulation for fertility preservation. DESIGN:Meta-analysis. SETTING:Not applicable. PATIENT(S):An electronic-based search was performed with the use of PubMed until May 2018 limited to English-language articles. In the final analysis, 10 case-controlled retrospective cohort studies were included, comparing ovarian response to stimulation between women with cancer and age-matched healthy women (control group). INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Number of total oocytes retrieved, number of mature oocytes, fertilization rate and two pronuclei embryos obtained. RESULT(S):Ten studies that included a total of 713 women with cancer were analyzed in the cancer group (722 cycles), and 1,830 healthy women (1,835 cycles) qualified as controls for the meta-analysis. The pooled results showed no impact of cancer diagnosis on the mean number of total oocytes (P=.517; 95% CI -0.23 to 0.12), mature oocytes (P=.104; 95% CI -0.23 to 0.01), and two pronuclei embryos (P=.136; 95% CI -0.32 to 0.04) and fertilization rates (P=.273; 95% CI -0.29 to 0.183). When the analysis was limited to women with breast cancer diagnosis, there was also no difference in the mean number of total oocytes (P=.812; 95% CI -0.28 to 0.36) and mature oocytes (P=.993; 95% CI -0.16 to 0.16) between the two groups. CONCLUSION(S):This meta-analysis indicates that cancer diagnosis is not associated with reduced response to ovarian stimulation.