Toward precision medicine for preserving fertility in cancer patients: existing and emerging fertility preservation options for women

Abstract

As the number of young cancer survivors increases, quality of life after cancer treatment is becoming an ever more important consideration. According to a report from the American Cancer Society, approximately 810,170 women were diagnosed with cancer in 2015 in the United States. Among female cancer survivors, 1 in 250 are of reproductive age. Anticancer therapies can result in infertility or sterility and can have long-term negative effects on bone health, cardiovascular health as a result of reproductive endocrine function. Fertility preservation has been identified by many young patients diagnosed with cancer as second only to survival in terms of importance. The development of fertility preservation technologies aims to help patients diagnosed with cancer to preserve or protect their fertility prior to exposure to chemo- or radiation therapy, thus improving their chances of having a family and enhancing their quality of life as a cancer survivor. Currently, sperm, egg, and embryo banking are standard of care for preserving fertility for reproductive-age cancer patients; ovarian tissue cryopreservation is still considered experimental. Adoption and surrogate may also need to be considered. All patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available in a timely manner, whether or not they decide to ultimately pursue fertility preservation. Because of the ever expanding number of options for treating cancer and preserving fertility, there is now an opportunity to take a precision medicine approach to informing patients about the fertility risks associated with their cancer treatment and the fertility preservation options that are available to them.

Keywords: Cancer; Chemo- or radiation therapy; Fertility Preservation; Oocyte; Precision Medicine; Technologies.

Fig. 1

Consequences of gonadotoxic treatment in reproductive-aged women. (A) The primordial follicle population—the ovarian reserve—can be represented by a parabolic curve across the female lifespan in which activation or death of primordial ovarian follicles occurs progressively with each menstrual cycle, from puberty to the menopause. Reprinted from Wallace and Kelsey [4]. (B–D) The growth of follicles with each cycle maintains hormonal balance necessary for overall women’s health. Gonadotoxic stress or treatment, such as chemotherapy or radiation therapy (red bar across all panels), induces a rapid decrease in the highly sensitive primordial follicles of the ovarian reserve (A, C), resulting in a follicle-depleted ovary (B) and premature ovarian failure (POF). Depletion of the ovarian reserve disrupts normal endocrine function and the production of hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, inhibin B, and inhibin A (D), leading to hormonal imbalance similar to that seen in postmenopausal women.

Fig. 2

Schema of fertility preservation approaches in cancer patients. Each procedure is marked with a line, either black (established) or blue (investigational). (A) Patients undergoing a natural or hyperstimulated cycle produce mature eggs that can be matured in vitro (IVM) and either cryopreserved or fertilized by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) to produce embryos that are cryopreserved. In patients who cannot undergo controlled ovarian stimulation (e.g., prepubertal girls or women with hormone-sensitive cancers) or in those who must start cancer treatment immediately, strips of ovarian cortex can be removed and cryopreserved, or individual follicles can be isolated from the tissues and cryopreserved. Investigational methods are focusing on use of thawed ovarian tissues for transplantation or in vitro growth of follicles, followed by IVM and IVF/ICSI. (B) During treatment, gonadotoxicity can be mitigated by the use of fertoprotective reagents that induce death in tumor cells while preventing off-target effects in other tissues, resulting in preserved fertility and endocrine function. (C) After cancer treatment, cryopreserved embryos can be thawed and transferred into the uterus, or cryopreserved eggs can be thawed and used for IVF/ICSI and the resulting embryos transferred to the patient. On the investigational side (blue arrows), cryopreserved follicles can be grown in culture, matured in vitro, and fertilized to produce embryos for transfer. Ovarian tissue can be transplanted back into the patient, or follicles can be isolated and used to produce embryos or cultured on a three-dimensional bioplotted scaffold as an artificial ovary for transplantation back into patients. Transplantation of ovarian tissue or follicles within an artificial ovary has the potential of restoring fertility as well as endocrine function after cancer treatment. (D) In patients who were unable to cryopreserve eggs, embryos, or ovarian tissue prior to treatment, researchers are now investigating the possibility of using oogonial stem cells (OSCs) to repopulate follicle-depleted ovaries, or differentiating follicle somatic cells and oocytes from embryonic stem (ES) cells or induced pluripotent stem (iPS) cells to assemble follicles de novo for transplantation or IVM and IVF/ICSI to create embryos for transfer.