2005 © Oxford University Press
Fertility Preservation: A Comprehensive Approach to the Young Woman With Cancer
Affiliation of authors: Center for Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York
Correspondence to: Kutluk Oktay, MD, Center for Reproductive Medicine & Infertility, 505 E 70th Street, Suite HT-340, New York, NY 10021 (e-mail: kuo9001{at}med.cornell.edu).
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ABSTRACT |
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 Top Abstract REVIEWEMBRYO CRYOPRESERVATIONOOCYTE CRYOPRESERVATIONOVARIAN CRYOPRESERVATION AND...SUMMARYReferences |
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Modern treatments for cancers of the reproductive age are yielding ever-higher cure rates, but more often than not, the price paid for survival is the loss of reproductive function from gonadal toxicity. Alkylating agents and ionizing radiation have well-recognized deleterious effects within the testes and ovary and cause sterility in a high proportion of patients exposed to these treatments. Preservation of fertility for men simply involves the banking of sperm before treatment, but for women, the storage of gametes is technically very complex and has limited success. Even when faced with the diagnosis of cancer, many reproductive-aged women are burdened by the possibility of never conceiving a child with their own eggs. Fertility preservation for the reproductive-age women with cancer is emerging as a challenging, but rewarding, application of assisted reproductive technologies such as in vitro fertilization. With recent advances in cryopreservation techniques, oocytes, embryos, and ovarian tissue can be banked from these patients before exposure to sterilizing chemotherapy and radiotherapy, providing future fertility options without compromising survival.
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REVIEW |
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Germ cells are inherently sensitive to the cytotoxic effects of chemotherapeutic agents. The effect of chemotherapy on female gonadal function is related to the type of agents used and their cumulative doses and to the patients' ovarian reserve (1,2). Ovarian reserve represents the population of primordial follicles within the ovary, which make up more than 90% of entire follicle population at any given time. Because ovarian reserve declines with age, older patients are more susceptible to chemotherapy; however, at least a fraction of ovarian reserve will be lost in all patients receiving gonadotoxic therapy, even if clinical and laboratory signs are not immediately apparent. Ovarian function can be maintained by as little as 10% of the ovary; thus, clinical measures of menstrual function are a poor assessment of ovarian damage. Cyclophosphamide and other alkylating agents are the most toxic for the ovary, producing an exponential decline in primordial follicle density with increasing dose (3). Compared to other regimens, cyclophosphamide-containing chemotherapies are four times more likely to result in short-term ovarian failure: Up to 77% of women experience such failure within 1 year (1). However, it can not be emphasized enough that even if reproductive function is maintained, these agents will surely shorten the patients' reproductive life spans.
To date, no therapies have been developed that are capable of protecting the ovary from the toxic effects of chemotherapy. Gonadotropin-releasing hormone agonists (GnRH-a's) have been used by some as chemoprotective agents, but they lack prospective evidence of their efficacy. In fact, the only prospective randomized study of their use showed no improvement in outcome compared to placebo (4). The hypoestrogenic state induced by these agents may actually have negative effects in breast cancer patients by arresting tumors cells in G0 phase and making them less responsive to chemotherapy (5,6). Assisted reproductive technologies are proving to be the only means of reliably offering these women pregnancy following sterilizing cancer treatments. On the basis of a patient's diagnosis, treatment protocol, and personal/social situation, an individualized plan can now be formulated for most patients. In this brief review, we address which reproductive technologies are presently available for the preservation of fertility in the reproductive age women and some of the challenges encountered with their application.
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EMBRYO CRYOPRESERVATION |
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Embryo cryopreservation is a widely used method of fertility preservation that has been available to cancer patients for several years. The only prerequisite for providing such a service is the ability to cryopreserve cleavage-stage embryos—a standard technique employed by in vitro fertilization (IVF) clinics for the banking of spare embryos and for situations in which the transfer of fresh embryos is contraindicated. Foremost is the requirement of a male partner unless the patient is prepared to use donated sperm. The other limitation to this method is the finite period of time the patient has to have her oocytes collected, such that her chance of a successful future pregnancy depends on the number of IVF cycles performed, and thus the number and quality of the embryos obtained. Using newer, short IVF protocols and appropriate doses of gonadotropins, both the embryo yield and number of attempts can be maximized. In the case of breast cancer, a period of 4–6 weeks between the time of surgery and chemotherapy is typical, allowing enough time for one or two attempts. Because all of the resources are at hand, many IVF clinics regularly cryopreserve embryos as a means of fertility preservation in patients with partners or donor sperm.
Breast cancer is the most common malignancy in reproductive-age women, with more than 180,000 new cases per year in the United States, and it makes up the majority of women seeking fertility preservation. Many of these tumors are estrogen receptor positive and, accordingly, are susceptible to situations of estrogen excess (7,8). Even those that are classified as being receptor negative will contain a small percentage of receptor-positive cells. Gonadotropin stimulation during IVF produces supraphysiologic estrogen levels, typically greater than 1000 pg/mL (peak natural cycle levels 200–350 pg/mL, depending on assay used) and not uncommonly in excess of 3000 pg/mL. Two strategies have been suggested to minimize this exposure to estrogen: oocytes can simply be recovered from an unstimulated (natural) cycle, or a chemoprotective agent can be included with a low-dose IVF protocol. Tamoxifen and aromatase inhibitors seem to be the best candidates, as they have a proven efficacy in the prevention of breast cancer recurrence and because, coincidentally, both have ovulation-inducing properties (9,10).
Tamoxifen is a selective estrogen receptor modulator with demonstrated efficacy in the treatment of estrogen receptor–positive breast cancer in postmenopausal women (9). Similar to clomiphene citrate, tamoxifen is an ovulation induction agent that competitively antagonizes estrogen receptors within the hypothalamus and pituitary, creating a perceived hypoestrogenic state and stimulating follicle-stimulating hormone (FSH) release via loss of negative inhibition by estrogens. By using tamoxifen as a single agent for 5 days or longer in the early follicular phase, one can obtain an average 1.6 embryos per cycle, compared with an average of 0.6 with a natural cycle (11). However, to maximize embryo yield, gonadotropins are required. With 150 U FSH per day and continuous use of tamoxifen (60 mg/day), we obtained an average of 5.1 embryos per cycle, compared with 1.6 with tamoxifen alone. The higher embryo yield came at the expense of estradiol levels in excess of 1000 pg/mL; however, tamoxifen likely afforded sufficient protection, with no difference in recurrence compared to unstimulated controls (12). In fact, elevated estradiol levels of this magnitude are common among premenopausal breast cancer patients receiving long-term tamoxifen treatment (13). Aromatase inhibitors, and specifically letrozole, have gathered recent popularity as ovulation-induction agents. Similar to tamoxifen, these agents stimulate endogenous FSH release by the creation of a hypoestrogenic state, but their most important role is in the suppression of estradiol levels during IVF.
With concomitant use of aromatase inhibitors, gonadotropin doses can be safely increased, at least in theory, to maximize embryo yield in breast cancer patients. The above agents should be used without prior GnRH-a down regulation; therefore, GnRH antagonists are required to prevent a spontaneous luteinizing hormone surge. Our preliminary experience with tamoxifen and letrozole in IVF indicates that they can both make embryo cryopreservation a safer and more widely available method of fertility preservation, but long-term follow-up will be needed to certify their safety and effectiveness.
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OOCYTE CRYOPRESERVATION |
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For children, adolescents, women without partners, or women wishing to retain their ability for paternity selection at the time of fertilization, oocyte cryopreservation is emerging as an option. Unfortunately, the technology is beset by lower pregnancy rates in comparison to embryo freezing, and despite recent encouraging advances, it has limited availability worldwide. Even in the patients with the best prognosis, pregnancy rates in leading cryopreservation centers do not exceed 20% per transfer, with rates typically reported of less than 2% per thawed oocyte. Low pregnancy rates relate to several technical challenges encountered during the freeze–thaw process and the in vitro maturation of immature oocytes. Mature oocytes provide the best chance for pregnancy but have several characteristics that make them susceptible to cryodamage. Because mature oocytes are arrested in metaphase II, the spindle apparatus is fully extended and prone to disassembly at lower temperature, with subsequent chromosome dispersion and aneuploidy (14,15). The oocyte's large size and high water content also make it vulnerable to ice crystal formation, rupture, and limited penetration of cryoprotectant solutions because of the low ratio of surface area to volume. With refinements in technique and better clinical outcomes, oocyte banking will prove to be a simple and versatile method of fertility preservation that, importantly, will provide women with independence when it comes to future paternity choices.
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OVARIAN CRYOPRESERVATION AND TRANSPLANTATION |
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Ovarian cryopreservation and transplantation is another option for patients seeking fertility preservation. Similar to oocyte freezing, a male partner is not required; thus, this method is an option for single patients. In children, ovarian cryopreservation is the only fertility-sparing option because ovarian stimulation and oocyte collection cannot be considered ethical. Many adult cancer patients will not have sufficient time to undergo ovarian stimulation for oocyte or embryo freezing, but ovarian tissue freezing can be done at any time during the cycle and does not require a delay in the chemotherapy. Any patient who will receive chemo- or radiotherapy that targets ovarian follicles can thus be considered a candidate for ovarian transplantation if her cancer has a low risk of ovarian metastasis (16). In addition, benign conditions that require chemotherapy, such as glomerulonephropathies and Behçet syndrome, can be considered, as well as benign disease of the ovary that requires oophorectomy for cure.
Since the first experiments with ovarian transplantation in animals, steady advances have been made in humans. Using oophorectomized sheep, Gosden et al. (17) demonstrated that normal menstrual function could be restored and spontaneous pregnancies achieved after autologous orthotopic transplantation of cryopreserved ovarian cortex. Since then, other species have been successfully transplanted with autologous ovarian tissue, as well as with human xenografts (18). With the knowledge gained from these experiments, trials in human transplantation were initiated.
Processing of the ovarian tissue begins with the cutting of cortical strips small enough to fit standard cryotubes and of a thickness of no greater than 2 mm, to allow for adequate penetration of the cryoprotectant solution. In the case of cancer patients, a thorough pathologic assessment of the tissue must be performed to exclude the presence of metastatic disease. Using modern cryopreservation techniques, viability can be retained in over 70% of the specimen. At an appropriate time after completion of the patient's cancer therapy, the tissue is thawed and transplanted either orthotopically within the pelvis or heterotopically within subcutaneous tissue (19–24). The latter technique is a standard method of parathyroid autotransplantation within the forearm (25). This is currently the method of choice for ovarian transplantation because it is minimally invasive, reversible, and repeatable and it permits easy access to the graft for monitoring follicle development or in the event of reoperation. The major disadvantage of transplanting ovarian strips is that revascularization of the graft occurs over several days and the consequent ischemia leads to partial fibrosis and the loss of more than 60% of the primordial population (17,26).
Administration of FSH has been shown to prolong survival of these grafts, but despite this, and depending on the patient's age, the life span of the grafts is always shorter than the in vivo life span of ovarian tissue. Grafts typically become hormonally active between 3 and 4 months after transplantation, at which time oocyte harvesting can be attempted, either with or without the aid of exogenous gonadotropins to stimulate follicle development.
Two significant achievements have been recently reported. Our group obtained the first viable embryo from a heterotopic transplant of cryopreserved ovarian cortex in a breast cancer survivor (27), and a live birth has been achieved following heterotopic transplantation of fresh ovarian cortex in a Rhesus monkey (28). Although this method is not widely available at present, significant progress is being made in laboratory and human ovarian transplantation trials, which may help the procedure become more widely acceptable. Among the most important questions facing researchers are How can we improve the follicle survival after ovarian transplantation? Can a healthy pregnancy accomplished after ovarian transplantation in humans? What will be the pregnancy rates?
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SUMMARY |
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TopAbstractREVIEWEMBRYO CRYOPRESERVATIONOOCYTE CRYOPRESERVATIONOVARIAN CRYOPRESERVATION AND...SUMMARYReferences |
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In general, young female cancer patients are poorly counseled on the effect of chemotherapeutic agents on the ovaries, as well as on their options for fertility preservation. Management of the cancer is of utmost importance, but several assisted reproductive technologies can provide the patient with the possibility of future pregnancies without compromising her cancer treatments. Recent strides in cryopreservation technology have made embryo banking more accessible and have given women real options for pregnancy after breast cancer: Although they are experimental at present, oocyte cryopreservation and ovarian tissue banking with transplantation are emerging as viable methods of fertility preservation in females subjected to medical treatments with potential effects on reducing fertility.
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