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Advances in cancer diagnosis and therapeutics have improved the prognosis with ovarian cancer, which has increased the potential for a good quality of life in survivors, especially adolescents and those of reproductive age. According to American Cancer Society, it is estimated that approximately 22,280 women will receive a new diagnosis of ovarian cancer and 14,240 women will die from it. Though most ovarian cancer is diagnosed in women of nonreproductive age, 12.1% of ovarian cancer patients are ≤44 years of age. The percentage of young women who survive ovarian cancer has increased as a result of improvements in diagnosis and earlier treatment; the overall 5-year survival rate for all ovarian cancers in women ≤44 years of age is 91.2% when it is found at stages 1A and 1B . Young women diagnosed with cancer are interested in preserving their fertility in addition to treating cancer; however, for women with ovarian cancer, it can be especially difficult to maintain reproductive function because the ovary is site of the primary cancer. Thus, ovary containing ovarian follicles becomes a target to be treated to remove cancer cells although it should be protected for fertility. Both ovarian cancer and the off-target effects of radiation and chemotherapy on the ovaries threaten fertility, making fertility preservation particularly challenge for this group of patients. Most cases involve surgical removal of the fallopian tubes and ovaries (unilateral or bilateral salpingo-oophorectomy) and removal of the uterus (hysterectomy). Furthermore, patients will get further steps such as radiation or chemotherapy to remove remaining cancer cells . This induces the death of ovarian follicles if patients keep one side of ovary during resection, resulting in loss of reproductive function in extreme case. Consequently, patients lose not only fertility but also endocrine system function and the protective effects of circulating estrogen, which can increase the risk of coronary disease, osteoporosis and cognitive dysfunction .
In the following sections, we discuss the currently available fertility preservation methods that may be applicable to some women with ovarian cancer, particularly those with unilateral disease. Ovarian cancers are generally classified as two categories dependent on origins; epithelial ovarian cancers (EOCs) and non-EOCs such as germ cell tumors, sex–cord–gonadal stromal tumors and borderline tumors. Among these, patients with early-stage EOC and borderline ovarian tumors, or those with juvenile granulosa cell tumors and germ cell tumors may be candidates for fertility preservation.
Data on the safety of fertility-sparing surgery  in young patients with early-stage ovarian cancer has been accumulating . Current technologies being used include the preservation of ovarian tissues that are taken during unilateral ovarian cancer surgery. The surgical techniques are extensively reviewed elsewhere ; briefly, during ovarian tumor resection, ovarian tissue is removed from the remaining ovary and cryopreserved for future usage. These cryopreserved tissues can be transplanted into patients after completion of cancer treatment.
As with ovarian tissue cryopreservation, oocytes from the ovarian tissues can be stored. Patients with unilateral ovarian cancer may wish to preserve oocytes in contralateral ovary due to the gonadotoxicity of chemotherapy to the ovarian reserve . Oocytes can be retrieved from the unaffected ovary during surgery, with or without controlled ovarian hyperstimulation. In ovarian cancer patients, transvaginal oocyte retrieval carries a risk of ovarian capsule rupture and cancer cell spillage, which can cause staging up from 1A to 1C. Moreover, controlled ovarian hyperstimulation (COH) can delay cancer treatment for a half month and may stimulate the rapid proliferation of hormone-dependent cancer cells such as those in granulosa cell tumor, and COH is not possible in prepubertal girls. Nevertheless, COH and intraoperative oocyte collection followed by cryopreservation has been used clinically for patients who have enough time for COH before undergoing surgery . Oocytes are stored as mature or immature oocytes. Immature oocytes are matured in vitro and then cryopreserved as mature oocytes.
For women who must undergo bilateral salpingo-oophorectomy, ovarian tissue and oocyte cryopreservation may not be possible and those who also undergo hysterectomy will need to consider other options, such as surrogacy, even if they have cryopreserved oocytes. Recently, successful uterine transplantation was reported , but application of this technique in clinical practice is still limited.
A primary concern regarding the autotransplantation of cryopreserved ovarian tissue in ovarian cancer survivors is the risk of reimplantation and dissemination of the primary cancer . The contralateral ovary may contain cancer cells in patients with unilateral ovarian cancer. Isolation of individual ovarian follicles from ovarian tissues and subsequent in vitro culture  may minimize the risk of transmission and reimplantation of malignant cells. Recently, mature human follicles have been successfully cultured in vitro to produce MII stage oocytes that could be used for IVF , suggesting that in vitro follicle culture is clinically applicable.
While in vitro culture of mature ovarian follicles is successful, one of the immature ovarian follicles is still in the experimental stage. Ovarian follicles in young girl cancer patients and cortical tissues from adult ovarian cancer patients are mostly primordial or primary follicles. Although these early stage of ovarian follicles can be isolated, they cannot be grown in vitro. Thus, this early stage of ovarian follicles should be activated using PTEN inhibitor or AKT activator , followed by in vitro ovarian follicle maturation. These follicles can be kept for future use.
In addition to fertility-sparing surgical approaches in early-stage ovarian cancer patients, methods are being developed to minimize the damage to germ cells (oocytes) caused by adjuvant chemotherapy and radiation therapy.
The most effective chemotherapeutic regimen for epithelial ovarian cancer is a combination of a platinum compound and a taxane. Platinum drugs, including cisplatin and carboplatin, have been in widespread use for treating both ovarian and testicular cancer . Cisplatin is one of the most efficient chemotherapeutic agents because it kills cancer cells through DNA damage and inhibition of DNA synthesis/replication. Cisplatin transferred into cells forms interstrand and intrastrand crosslinks, making platinum-DNA adducts [14,15]. DNA damage caused by platinum drugs stimulates signal transduction pathways involved in cell death.
Radiation is reserved for chemotherapy-resistant ovarian cancers. Lower doses of radiation therapy are used for ovarian cancers, resulting in germ cell death in the contralateral ovary in the case of unilateral oophorectomy.
Germ cells are the most sensitive cells in the body to radiation and chemotherapy [16,17]. The reason for the high sensitivity is assumed to be related to the presence of TAp63 molecule , a member of Trp53 family and a main molecule of the apoptotic pathway. TAp63, as a guardian of germ cells, decides the fate of cells depending on the intensity of DNA damage. It is thought that this is a unique phenomenon in female germ cells that protects genetic material transmission from generation to generation . c-Abl, an upstream molecule, has been shown to regulate TAp63 . Through understanding the precise pathway of germ cell death and targeting the pathway, germ cells can be protected from the off-target effects of radiation and chemotherapy.
Developing fertoprotective agents has long been studied to protect oocytes against radiation and chemotherapy. Gonadotropin-releasing hormone (GnRH) antagonists and agonists, sphingosine-1-phosphate (S1P), imatinib mesylate, amifostin and tamoxifen  have been proposed for this function. Imatinib mesylate can be used for protecting oocytes through blocking c-Abl molecule in oocytes-death pathway against cisplatin . Moreover, amifostin can be a good fertoprotectant to protect apoptosis in oocytes when patients get cancer treatment as shown from the cytoprotective effects of amifostine against cyclophosphamide . However, none of these drugs have been tested to protect oocytes in mice carrying ovarian cancer or human. Therefore, it is necessary to test these candidate agents or clinically used drugs as well as develop new and efficient fertoprotective agents in preservation of ovarian reserve for ovarian cancer patients.
For young women with ovarian cancer, it is especially important to consider treatment approaches that incorporate both ovarian cancer treatment and fertility preservation. For these women, because the ovary is the source of fertility and the site of the primary cancer, the challenge is to simultaneously remove and eliminate cancer cells and protect and preserve healthy oocytes. The fertility preservation options available to women with ovarian cancer will be dependent on the stage, type and location of the cancer; therefore, collaboration within multidisciplinary teams of general gynecologists, gynecologic oncologists, embryologists, operating room staff and reproductive endocrinologists are necessary to help patients preserve their fertility and future quality of life.
The authors thank SC Tobin, MH Cordeiro and ME Edmonds for giving comments on the manuscript and editing the manuscript.
Financial & competing interests disclosure
This work was supported by the Center for Reproductive Health After Disease (P50HD076188) from the NIH National Center for Translational Research in Reproduction and Infertility (NCTRI; to SY Kim) and by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C0055; to JR Lee). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.