Faculty Bibliography

Purpose To provide current recommendations about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from January 2013 to March 2017 was completed using PubMed and the Cochrane Library. An Update Panel reviewed the identified publications. Results There were 61 publications identified and reviewed. None of these publications prompted a significant change in the 2013 recommendations. Recommendations Health care providers should initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible. Providers should be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, providers should advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm, oocyte, and embryo cryopreservation are considered standard practice and are widely available. There is conflicting evidence to recommend gonadotrophin-releasing hormone agonists (GnRHa) and other means of ovarian suppression for fertility preservation. The Panel recognizes that, when proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, GnRHa may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. GnRHa should not be used in place of proven fertility preservation methods. The panel notes that the field of ovarian tissue cryopreservation is advancing quickly and may evolve to become standard therapy in the future. Additional information is available at www.asco.org/survivorship-guidelines .

BACKGROUND:Aromatase inhibitors (AI) have been introduced to reduce estrogen exposure in women with estrogen-sensitive cancer undergoing ovarian stimulation for oocyte/embryo cryopreservation. There have been questions regarding whether the addition of AI and the presence of BRCA mutations affect cycle outcomes. We sought to determine the impact of letrozole and BRCA mutations on fertility preservation (FP) cycle outcomes of patients undergoing ovarian stimulation with an antagonist protocol. METHODS:The data were generated by the secondary analysis of a prospective database of all females diagnosed with cancer who underwent embryo or oocyte cryopreservation for FP. The final analysis included 145 patients stimulated with an antagonist protocol either using letrozole combined with recombinant follicle-stimulating hormone (rFSH; LF, n = 118) or rFSH alone (FA, n = 24). RESULTS:The mean number of total (15.6 [7.9] vs 10.2 [7.8]; P = .004) and mature oocytes (10.4 [5.1] vs 7.8 [3.5]; P = .044) and embryos frozen (7.7 [5.3] vs 5.3 [2.7]; P = .043) were significantly higher after LF stimulation versus FA. In the LF group, women with BRCA mutations produced significantly fewer oocytes (11.0 [8.0] vs 16.4 [7.7], P = .015) and embryos (5.1 [4.4] vs 8.2 [4.7], P = .013), compared to those who were mutation negative. After adjusting for age, body mass index, baseline FSH level, and BRCA status, LF protocol still resulted in higher number of total oocytes (95% confidence interval [CI]: 1.9 to 3.6; P = .002) mature oocyte (95% CI: 0.3 to 1.4; P = .028), and embryo yield (95% CI: 0.7 to 1.4; P = .015). CONCLUSION:In women with cancer undergoing FP, letrozole appears to enhance response to ovarian stimulation while the presence of BRCA mutations is associated with lower oocyte and embryo yield.

In tissue engineering, decellularized scaffolds have been proved to have remarkable capacity to promote regeneration in various organs such as kidney, heart, lung, and liver. Marrying the field of cryobiology and reproductive medicine resulted in considerable progress and breakthroughs, which led to the emergence of ovarian tissue cryopreservation and transplantation as a promising option for fertility preservation. Here we describe an innovative application of decellularized tissue scaffolds as a regenerative platform for reconstruction of ovarian grafts for auto-transplantation.

Context:Recent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking. Objective:To determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage. Design:A comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers. Setting:Two academic centers. Patients or Other Participants:Of the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls. Intervention:Histology and immunohistochemical analysis on paraffin-embedded ovarian sections. Main Outcome Measure(s):Primordial follicle density and the percentage of DNA double-strand break (DSB)-positive primordial follicle oocytes. Results:Ovaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both BRCA1 and BRCA2 mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and BRCA1 mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years. Conclusions:We provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.

CONTEXT:Ovarian cryopreservation followed by autotransplantation is still considered an experimental strategy for fertility preservation (FP) mainly because the success rates are unknown. OBJECTIVE:To determine cohort epidemiologic characteristics and success rates of autologous ovarian tissue transplantation (OTT) with previously cryopreserved tissue. MATERIALS AND METHODS:Literature review from 1999 to October 1, 2016. Additional cases were retrieved from meeting abstracts and own database. We selected studies that reported autologous OTT with previously banked tissue in humans. We did not include any cases involving fresh ovarian tissue transplantation or those performed to treat idiopathic premature ovarian failure/insufficiency. Both authors reviewed and selected studies for eligibility, which resulted in 59 full-text studies assessed for eligibility. Cases were extracted from original reports and reviews by the junior author, and the senior author reviewed and verified the extracted data. RESULTS:Nineteen reports were included for qualitative synthesis. In 10 studies, detailed data were available to determine clinical and live birth + ongoing (LB + OG) pregnancy as well as endocrine restoration rates. Three hundred nine OTTs were performed with cryopreserved tissue, resulting in the birth of 84 children and 8 OG pregnancies. The cumulative clinical and LB + OG rates were 57.5% and 37.7%, respectively, and the endocrine restoration rate was 63.9%. CONCLUSION:Success rates with cryopreserved OTT have reached promising levels. Given these recent data, ovarian tissue cryopreservation should be considered as a viable option for FP.

STUDY OBJECTIVE:To show a new approach for orthotopic human ovarian tissue transplantation via robot-assisted laparoscopic surgery. DESIGN:A step-by-step video explanation of the surgical technique (Canadian Task Force classification III). SETTING:Academic medical center. INTERVENTIONS:The robot-assisted transplantation approach consisted of 3 steps: (1) reconstruction of the ovarian tissue graft, (2) preparation of the contralateral menopausal ovary as the recipient site, and 3) transplantation of the reconstructed graft to the bivalved contralateral ovary. Institutional review board approval was obtained. MEASUREMENTS AND MAIN RESULTS:Although still experimental, cryopreservation and subsequent transplantation of frozen-thawed ovarian tissue are currently the only available methods for prepubertal girls and young women with cancer who are not eligible for established fertility preservation options such as oocyte or embryo cryopreservation [1]. We performed the first reported autologous ovarian transplantation with a conventional laparoscopic technique [2]. To date, over 60 babies have been born after the orthotopic transplantation of cryopreserved ovarian tissue, and this number is growing [3,4]. Until recently, all of these children were born from ovarian transplants that were performed via laparotomy or conventional laparoscopy [5]. We have recently developed a robot-assisted ovarian transplantation procedure that uses an extracellular matrix scaffold to facilitate ovarian reconstruction, handling, and revascularization. Both of the procedures resulted in robust ovarian function and births [6]. The purpose of this video reports the surgical technique in detail, which uses the da Vinci Xi (Intuitive Surgical Inc, Sunnyvale, CA) robotic system for transplantation, and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp, Branchburg, NJ) for graft reconstruction. CONCLUSION:Robotic ovarian transplantation may have several advantages, which include precision, more delicate graft handling, and reduced time from tissue thawing to transplantation. The collective usefulness of the extracellular tissue matrix may enhance this technique by enabling a niche for ovarian reconstruction and potentially enhanced revascularization. The feasibility and comparative advantages of this technique are currently being studied in ongoing trials.

On average, over 25000 women are diagnosed with breast cancer under the age of 45 annually in the United States. Because an increasing number of young women delay childbearing to later life for various reasons, a growing population of women experience breast cancer before completing childbearing. In this context, preservation of fertility potential of breast cancer survivors has become an essential concept in modern cancer care. In this review, we will outline the currently available fertility preservation options for women with breast cancer of reproductive age, discuss the controversy behind hormonal suppression for gonadal protection against chemotherapy and highlight the importance of timely referral by cancer care providers.

Robotic technology is one of the most promising and rapidly developing advancements of the twenty-first century with a potential to make significant contributions to reproductive surgery and preservation of fertility. Along with the major advances in cancer therapy, the number of female cancer survivors of reproductive age has dramatically increased. As a consequence, fertility preservation has gained more emphasis in reproductive science in the last few decades. A broad range of surgical procedures such as tubal reanastomosis, ovarian transposition, radical trachelectomy, and ovarian transplantation has been introduced to restore or preserve fertility in selected patients. These procedures can be accomplished through various surgical routes, including open surgery and minimally invasive approaches. In this review, we aim to present the current applications, advantages, and disadvantages of robotic technology in the field of reproductive surgery with a special interest in ovarian transplantation for fertility preservation.