Clinical Review

Freezing the biological clock: A 2023 update on preserving fertility

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To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.5 Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.6 An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.7

Referral for fertility preservation

Since 2006, the American Society of Clinical Oncology recommended, as part of the consent prior to therapy, oncologists should address the possibility of infertility with patients “as early in treatment planning as possible” and “...Fertility preservation is an important, if not necessary, consideration when planning cancer treatment in reproductive-age patients.”


1. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24:2917-2931.

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),8 initially being used for patients with cancer and now also including women desiring POC.

Ovarian and embryo cryopreservation. Ovarian stimulation and egg retrieval for OC can now occur within 2 weeks due to a random start protocol whereby women can begin ovarian stimulation any day in their cycle (ie, preovulation or postovulation).9

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.10

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.11 Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.12 However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.15 In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.16

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.17 Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...


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