Molecular and Cellular Endocrinology 187 (2002) 83 – 91 Protecting female fertility from cancer therapy Ariel Revel *, Neri Laufer Department of Obstetrics and Gynecology, Hadassah Uniersity Hospital, Kiryat Hadassah, Jerusalem, Israel Abstract Recent advances in cancer therapy have improved the long-term survival of young cancer patients who are then commonly faced with iatrogenic infertility and premature ovarian failure. Preservation of fertility potential has thus become a major goal and could be realized by preventing ovarian toxicity or by cryopreservation of reproductive cells (i.e. oocytes, embryos) and tissues (i.e. ovarian cortex). GnRH analogs prevent chemotherapy-induced-ovarian-damage in rats, however human results are controversial. Anti-apoptotic agents (i.e. sphingosine-1-phosphate) may present an innovative treatment to prevent oocyte destruction during cancer therapy. Although cryopreservation of mouse oocytes is successful, the results obtained in other mammalian species were worse, probably due to their extreme sensitivity to suboptimal conditions during the process of cryopreservation. This resulted in low oocyte survival and fertilization rates, a high incidence of polyploidy, and poor embryonic developmental ability. Ovarian tissue cryopreservation is currently considered as the optimal procedure for follicle banking. Transplantation offers the best prospect of using frozen-thawed ovarian tissue, since no reliable ovarian in-vitro culture technology exists. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cancer therapy; Cryopreservation; Oocyte; Ovarian tissue; Primordial follicle; Transplantation; GnRH analog; Culture www.elsevier.com/locate/mce 1. Patients undergoing cancer treatment are at risk of ovarian failure Treatment of malignant disease has resulted in a significant increase in life expectancy for young cancer patients (Boring et al., 1991), it is estimated that at least 1:1000 adults are childhood cancer survivors (Birch et al., 1988). This has resulted in a rising interest in improving the life quality of patients who overcome this disease. Female sterility resulting from oocyte de- struction is an unfortunate, and in many cases in- evitable, consequence of chemotherapy. Females are particularly at risk to gonadal toxicants since, unlike males, females are born with an irreplaceable supply of germ cells in their ovaries. Natural selection processes further reduce this precious reserve such that by the time of puberty, when eggs could actually be used for fertilization and pregnancy, their number has been de- pleted to less than three-quarters of the starting cohort. In the human female, the completely natural loss of oocytes eventually leads to near-exhaustion of the germ cell stock around the fifth decade of life, and the menopause ensues. Consequently, exposure of women to potentially damaging agents, such as anti-cancer drugs, industrial chemicals or even cigarette smoke, can have a dramatic and irreversible effect on the ovary by accelerating the natural process of germ cell depletion and, as a direct consequence, advance the time to menopause. Older age is correlated with an increased risk of ovarian failure. In contrast, younger age may predict return of ovarian function in 30% of patients 6–48 months after therapy (Schimmer et al., 1998). The clinical observation that older women appear to be more affected by exposure to chemotherapy can be explained by the fact that older women naturally have a smaller ovarian reserve to start with. Therefore, an apparent resumption of ovarian function after cancer therapy does not rule out a significant reduction in the ovarian reserve. These patients should not delay child- bearing, given the real risk of premature ovarian failure (POF). Nevertheless, anti-cancer treatment severely de- pletes the follicular store even in young patients (Byrne et al., 1987) resulting in menstrual irregularities, ovarian failure and associated infertility (Chapman et al., 1979; Clark et al., 1995; Horning et al., 1981). Histologic studies have shown that the end result of chemotherapy on human ovarian tissue is ovarian atro- * Corresponding author. Tel.: +972-2-776-424/5; fax: +972-2- 432-445. 0303-7207/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(01)00705-5