Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:This study aims to review the current state of different fertility preservation options in patients facing the risk of gonadal failure. RECENT FINDINGS/RESULTS:Various malignant and nonmalignant diseases have been successfully treated with high-dose chemotherapy or radiotherapy. Even though many young patients receiving these treatments are at risk of developing reproductive failure, a number of fertility preservation options ranging from embryo cryopreservation to ovarian tissue cryopreservation are now available. SUMMARY/CONCLUSIONS:Embryo cryopreservation is a well established technique to preserve fertility. The success rate with oocyte cryopreservation has been on the rise. Both oocyte and embryo freezing require ovarian stimulation and novel ovarian stimulation regimens utilizing aromatase inhibitors which have been developed for ovarian stimulation in women with estrogen sensitive cancer. Even though ovarian tissue cryopreservation is a novel technology, it is the only fertility preservation option for children and the only treatment strategy that can restore ovarian function. In-vitro maturation is a promising technology and can be applied in combination with ovarian tissue cryopreservation.

OBJECTIVE:To determine whether addition of taxanes to anthracycline and cyclophosphamide regimens impact ovarian function as assessed by menstrual history and ovarian reserve markers. DESIGN/METHODS:Prospective observational analysis. SETTING/METHODS:Large university fertility center. PATIENT(S)/METHODS:Forty-five women with a history of breast cancer of stages I-IIIA who either received anthracycline, cyclophosphamide, and paclitaxel (ACT) or received anthracycline with cyclophosphamide (AC). INTERVENTION(S)/METHODS:Menstrual histories were obtained at 6 months and at a mean of 28 months after chemotherapy. Early follicular phase FSH and E(2) samples were obtained at the second follow-up. MAIN OUTCOME MEASURE(S)/METHODS:Incidence of amenorrhea and abnormal laboratory values. RESULT(S)/RESULTS:There was no statistically significant difference in the rates of amenorrhea at 6 months after chemotherapy (AC group, 41.7%; ACT group, 29%). At the second follow-up, a mean of 28 months after chemotherapy, there was a trend toward higher amenorrhea in the ACT patients (35.7%, vs. 9.1% in the AC group). When the ovarian markers were included, an additional eight menstruating patients were identified with abnormally elevated FSH or E(2) levels. CONCLUSION(S)/CONCLUSIONS:We found no significant long- or short-term impact of taxanes on rates of amenorrhea. Future studies on the reproductive effects of chemotherapeutic agents should incorporate ovarian reserve markers, because menstrual history alone may underestimate the impact of these cytotoxic agents.

In this Practice Point commentary, we discuss the results and limitations of a nonrandomized, retrospective-prospective study of gonadotropin-releasing hormone analogs (GnRHa) in women with Hodgkin disease. Blumenfeld et al. concluded that coadministration of GnRHa during chemotherapy preserved cyclic ovarian function but not fertility. As the endocrine and ovulatory functions of the ovary are connected, this conclusion seems implausible. The study did not control for disease severity or the dose of alkylating agents. In addition, GnRHa treatment was not randomized, so patients in the control group were unlikely to have received GnRHa because the severity of their disease resulted in more-aggressive chemotherapy. By contrast, the only randomized study published to date showed no gonadal protection from GnRHa during chemotherapy in either sex. Furthermore, GnRHa did not prevent primordial-follicle loss in a human ovarian xenograft model. Unless a larger prospective study proves otherwise, GnRHa should not be offered as a proven method of fertility preservation.

PURPOSE OF REVIEW/OBJECTIVE:The purpose of this study is to review the impact of chemotherapy on fertility and to update the reader on the current state of fertility preservation techniques. RECENT FINDINGS/RESULTS:Chemotherapy results in irreversible damage to ovarian follicles and stromal function, and alkylating agents cause the most significant damage to ovarian reserve. Options for fertility preservation range from well established techniques such as embryo cryopreservation to experimental ones such as ovarian tissue freezing. The safety and effectiveness of concomitant use of gonadotropin-releasing hormone analogues to prevent chemotherapy-induced follicle death is still debated. In-vitro maturation of germinal vesicle oocytes can be an option in patients who do not have sufficient time for ovarian stimulation. SUMMARY/CONCLUSIONS:The impact of chemotherapy on future fertility is much more significant than is widely believed. Because of this, young females should be counseled about fertility preservation options. Fertility preservation requires an individualized approach. If possible these patients should be encouraged to utilize the most established assisted reproductive techniques. Although success of IVF with frozen-thawed embryos now approaches that of using fresh embryos, success rates with oocyte freezing are lower but these rates are on the rise. Even though ovarian tissue cryopreservation is still an experimental technique, currently it is the only fertility preservation option in children.

PURPOSE/OBJECTIVE:Because of the accompanying increase in estrogen levels, safety of performing in vitro fertilization (IVF) in women with breast cancer is unknown. Our goal was to determine the effect of controlled ovarian stimulation (COS) using a combination of letrozole with standard fertility medications on disease-free survival in women undergoing embryo or oocyte cryopreservation before adjuvant chemotherapy. PATIENTS AND METHODS/METHODS:A total of 215 women with breast cancer were prospectively evaluated for fertility preservation before adjuvant chemotherapy. Of those, 79 elected to undergo COS with letrozole and gonadotropins for embryo or oocyte cryopreservation. The remaining 136 patients underwent no fertility-preserving procedure and served as controls. RESULTS:Study and control groups were similar at enrollment except for a trend for higher estrogen-receptor positivity in the COS group (P = .08). Time between surgery and chemotherapy was longer for IVF patients (45.08 v 33.46 days; P < .01). Peak estradiol levels ranged from 58.4 to 1,166 pg/mL (mean, 405.94 +/- 256.64 pg/mL or 1,486.76 +/- 942.13 pmol/L) in COS patients. The median follow-up after chemotherapy was 23.4 months (range, 7.5 to 63.6 months) in the COS group and 33.05 months (range, 4.5 to 63.6) in the control group. The hazard ratio for recurrence after IVF was 0.56 (95% CI, 0.17 to 1.9), and the survival was not compromised compared with controls (P = .36). CONCLUSION/CONCLUSIONS:Ovarian stimulation with gonadotropins and letrozole for the purpose of fertility preservation is unlikely to cause substantially increased recurrence risk. Further research, including longer-term follow-up is needed to confirm these findings.

Stem cells, with their unlimited self-renewal feature and their ability to differentiate into almost every mature cell type in the body, have enormous potential for research and therapeutic application. In this article, we review the formation of primordial germ cells, the precursors of adult gametocytes, from their specification to their migration to prospective gonads. We discuss recent studies that obtained germ cells from stem cells in vitro. We place special emphasis on studies that challenge the current dogma in reproductive biology that female mammals are born with a set number of nonrenewable germ cells in the ovary by showing germ cell renewal in the adult ovary.

A prerequisite to the understanding of the ovarian diseases and infertility is a thorough understanding of normal embryology and physiology of the ovary. Therefore, the objective of this review article is to provide brief and updated information on the molecular basis of the events that control gonadal development, germ cell formation, folliculogenesis, and ovulation.

Mitogen-activated protein kinases (MAPKs) are components of signaling cascades regulated by environmental stimuli. In addition to participating in the stress response, the MAPKs c-Jun N-terminal Kinases JNK1 and JNK2 regulate the proliferation of normal and neoplastic cells. JNKs contribute to these processes largely by phosphorylating c-Jun and thus contributing to the activation of the AP-1 complex. We here report that JNKs control entry into mitosis. We have observed that JNK activity and phosphorylation of c-Jun become elevated during the G2/M transition of the cell cycle in immortalized fibroblasts and ovarian granulosa cells. Pharmacological inhibition of JNK causes a profound cell cycle arrest at the G2/M transition in both cell types. This effect is specific as it occurs with two distinct small molecule compounds. Inactivation of JNK prior to mitosis prevents expression of Aurora B and phosphorylation of Histone-H3 at Ser 10. Silencing of JNK1 and 2 causes a similar effect, whereas overexpression of JNK1 and 2 causes the opposite effect. Inhibition of JNK delays activation of cdc-2 and prevents downregulation of Cyclin B1. We conclude that JNK signaling promotes entry into mitosis by promoting expression of Aurora B and thereby phosphorylation of Histone-H3.

OBJECTIVE:To report a novel approach to fertility preservation by in vitro maturation and embryo cryopreservation after LH surge and ovulation. DESIGN/METHODS:Case report. SETTING/METHODS:Two university-based reproductive endocrinology clinics. PATIENT(S)/METHODS:Forty-year-old woman with breast cancer seeking fertility preservation before chemotherapy. INTERVENTION(S)/METHODS:The plan was ovarian stimulation and retrieval of mature oocytes, followed by IVF; however, premature LH surge and ovulation occurred before oocyte retrieval. Because no mature oocyte was recovered, follicles <10 mm in diameter were also aspirated. MAIN OUTCOME MEASURE(S)/METHODS:Recovery of immature oocytes after ovulation, in vitro maturation of these oocytes, and fertilization and vitrification of generated embryos. RESULT(S)/RESULTS:Four immature oocytes were recovered, and two matured in vitro. After fertilization with intracytoplasmic sperm injection, embryos progressed to the four-cell stage on day 2 and were vitrified for future use. CONCLUSION(S)/CONCLUSIONS:This case illustrates that under time constraints, immature oocytes can be recovered after ovulation and used to generate embryos for fertility preservation.

Every year thousands of young teenagers are afflicted with different types of cancer and receive gonadotoxic chemotherapy and radiotherapy regimens, causing depletion of germ cells in the gonads and premature gonadal failure. In this review, we discuss and outline the current strategies and the future directions of fertility preservation and ovarian cryopreservation and transplantation in adolescents and young females.