From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.1 Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.
Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation2,3 with rapid implementation.
Dr. Mark P. Trolice
One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.
Dr. Kutluk Oktay
Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?
A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.4 A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin4 induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.6 When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.7 Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.10
In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.4
Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?
A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine11 with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.10 Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.7 Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.