Fertility preservation options for female patients with malignancies

PURPOSE OF REVIEW: Preservation of fertility in female patients diagnosed with cancer has recently been an area of intensive investigation. This review summarizes available options and discusses recently published data concerning experimental methods. Specific strategies for fertility preservation in women with gynecologic malignancies are also presented. RECENT FINDINGS: Success with ovarian stimulation protocols using tamoxifen or aromatase inhibitors has recently been reported for women with breast cancer who attempt embryo cryopreservation prior to chemotherapy. The first embryo transfer using oocytes retrieved from cryopreserved ovarian tissue implanted at a heterotopic location, the first pregnancy following orthotopic transplantation of cryopreserved ovarian tissue, and increasing success with oocyte cryopreservation were also reported. SUMMARY: Fertility preservation in female patients with cancer has become an important health issue due to increasing survival rates and delayed childbearing especially in Western countries. Radical vaginal trachelectomy for cervical cancer, conservative surgery for ovarian tumors, and progestin treatment in endometrial cancers may be considered at early stages in order to preserve fertility. Embryo cryopreservation is an established technique that is available for fertility preservation, providing a delay in the initiation of chemotherapy or radiotherapy is acceptable, and a partner or donor sperm is available. Additional techniques that could be offered after counseling the patient about their experimental nature include oocyte cryopreservation, ovarian cryopreservation, and gonadotropin-releasing hormone agonist co-treatment with chemotherapy. Improvement of these techniques as well as better characterization of their success rates and risks await further investigation.     

Y a-t-il une place pour la cryopréservation ovocytaire après le traitement du cancer ?

The number of young cancer women theoretically eligible for fertility preservation before chemotherapy is steadily increasing. Nevertheless, the number of patients who can really benefit from complex ART techniques such as ovarian tissue or oocyte/embryo cryopreservation remains very low mainly because of a too short time-interval between the cancer diagnosis and its treatment. Lack of adequate information regarding post treatment infertility risk and logistical difficulties to access to a highly specialized cryopreservation centre are also reasons of importance. It is now well-established that these patients are at high risk of infertility even if they return to a normal ovarian function. Therefore, for patients who could not benefit from fertility preservation before cancer treatment, and who have recovered spontaneous menstrual cycle, one might raise the question of oocyte freezing once the cancer cured.     

Oocyte/embryo cryopreservation before chemotherapy for breast cancer

Breast cancer affects 6300 new patients per year under age 40 per year in France. The new adjuvant chemotherapy protocols have significantly improved the prognosis of these young women who may wish to conceive later. Embryo cryopreservation is the best way to preserve fertility, providing 25 to 35% chance of pregnancy. Oocyte freezing may be an alternative for single patients. This review will focus on: (1) ovarian toxicity of new adjuvant chemotherapy protocols, (2) the place of embryo or oocyte cryopreservation in fertility preservation techniques, (3) indications and protocols.     

Human oocyte and ovarian tissue cryopreservation and its application

PURPOSE: To review the recent progress in human oocyte and ovarian tissue cryopreservation, and in the application of these two technologies for preserving female fertility of patients who are undergoing cancer treatment. DESIGN: The literature on human oocyte and ovarian tissue freezing was searched with PubMed. The scientific background, current developments and potential future applications of these two methods were reviewed. RESULTS: Chemotherapy and/or radiotherapy can induce premature ovarian failure in most of female cancer patients. Consequently, there has been a greater need for options to preserve the reproductive potential of these individuals. However, options are somewhat limited currently, particularly following aggressive chemotherapy and/or radiotherapy treatment protocols. In recent years, there have been considerable advances in the cryopreservation of human oocytes and ovarian tissue. For women facing upcoming cancer therapies, cryopreservation of ovarian tissue and oocytes is a technology that holds promise for banking reproductive potential for the future. Recent laboratory modifications have resulted in improved oocyte survival, oocyte fertilization, and pregnancy rates from frozen-thawed oocytes in IVF. This suggests potential for clinical application. CONCLUSIONS: In the case of patients who are facing infertility due to cancer therapy, oocyte cryopreservation may be one of the few options available. Ovarian tissue cryopreservation can only be recommended as an experimental protocol in carefully selected patients. In ovarian tissue transplantation, more research is needed in order to enhance the revascularization process with the goal of reducing the follicular loss that takes place after tissue grafting. These technologies are still investigational, although tremendous progress has been made. The availability of such treatment will potentially lead to its demand not only from patients with cancer but also from healthy women who chose to postpone childbearing until later in life and therefore wish to retain their fertility.     

Fertility preservation in women with breast cancer

Fertility preservation is an important issue for young women diagnosed with breast cancer. The most well-established options for fertility preservation in cancer patients, embryo and oocyte cryopreservation, have not been traditionally offered to breast cancer patients as estradiol rise during standard stimulation protocols may not be safe for those patients. Potentially safer stimulation protocols using tamoxifen and aromatase inhibitors induce lower levels of estradiol whereas similar results in terms of number of oocyte and embryo obtained to standard protocols. Cryopreservation of immature oocytes and ovarian cortical tissue, both still experimental methods, are also fertility preservation options for breast cancer patients.     

Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients

As cancer treatment outcomes improve, the number of women with cancer seeking fertility preservation increases. Currently, embryo/oocyte cryopreservation appears to provide the best fertility preservation option. However, patients may not have sufficient time to undergo ovarian stimulation prior to chemotherapy and/or the hormones used in ovarian stimulation are contraindicated for certain tumours. In-vitro maturation has been suggested as an effective treatment for these patients. This report presents three women aged 21, 30 and 40 years, without male partners, seeking fertility preservation prior to chemotherapy. They were first seen during the luteal phase of their menstrual cycle and were to undergo gonadotoxic treatment imminently. They underwent immature oocyte retrieval in the luteal phase and seven, five and seven immature oocytes were recovered, respectively. After in-vitro maturation, five, three and five metaphase II (MII) oocytes were vitrified. Two patients later underwent one and two more retrievals, respectively, in the follicular phase of the next cycle(s) and additional oocytes were cryopreserved. These results suggest that immature oocytes recovered in the luteal phase can successfully be matured in vitro; therefore, if there is not sufficient time for conventional follicular-phase oocyte retrieval in a stimulated/unstimulated cycle prior to chemotherapy, a retrieval in the luteal phase could be considered.     

Fertility preservation options for women with malignancies

Cancer is not rare in younger women. There has been a remarkable improvement in the survival rates due to progress in cancer treatment. The necessary treatment for most of the common cancer types occurring in younger women implies either removal of the reproductive organs or cytotoxic treatment that could partially or definitively affect reproductive function. Early loss of ovarian function not only puts the patients at risk for menopause-related complications at a very young age, but is also associated with loss of fertility. Further, women in the western hemisphere have been delaying initiation of childbearing to later in life. The results of these changes have led to an increase in patients facing the risk of premature ovarian failure, and therefore seeking help in preserving their fertility. This increase in demand has resulted in a proliferation of techniques to preserve fertility. Indeed, the number of options is increasing; some are more established procedures, such as embryo cryopreservation, and some are still experimental, such as ovarian cryopreservation. Because of the variations in type and dose of chemotherapy, the type of cancer, the time available before onset of treatment, the patient's age and the partner status, each case is unique and requires a different strategy of fertility preservation. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall the potential early loss of ovarian function secondary to radiotherapy and/or chemotherapy for cancer at a young age; explain the increasing demands for fertility preservation; and summarize the limited number of proven, safe, and efficacious methods.     

Present and future fertility preservation strategies for female cancer patients

As survival rates with cancer treatment are steadily increasing, many women are now facing sterility due to treatment induced ovarian failure. This review will attempt to summarize the options for trying to preserve fertility in these patients. The optimal approach depends on the type of cancer, the type of treatment (e.g., radiation and/or chemotherapy), time available till onset of treatment, patient's age, and whether the patient has a partner. Ovarian transposition remains the standard of care for women undergoing pelvic radiation, although it has been suggested that it may be combined with ovarian tissue cryopreservation. For patients about to receive chemotherapy or whole body radiation, in vitro fertilization (IVF) with embryo cryopreservation is a well established treatment with a good success rate. However, it requires delaying cancer treatment for 2 to 4 weeks and a partner or willingness to use donor sperm. When these criteria cannot be met, more experimental options include oocyte cryopreservation for later IVF and ovarian tissue cryopreservation. The tissue may be autotransplanted back to the pelvis, when the patient is in remission, to attempt spontaneous conception or subcutaneously for easy access of follicle aspiration for IVF. Alternatively, it may be xenografted to immunocompromised mice to induce follicle maturation in preparation for retrieval for IVF. Emerging treatment options for fertility preservation include medication to prevent chemotherapy-induced oocyte damage and oocyte construction from somatic cell nuclei. IVF with donor oocyte remains an established option with a very high success rate for those who fail to conceive with the above measures or who elect not to avail themselves to experimental procedures. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to demonstrate knowledge about fertility preservation when counseling appropriate female cancer patients, recall current clinical strategies to assist women cancer patients to try to maintain their fertility if they wish, and appraise future strategies as they develop.     

Ovarian stimulation protocols for onco-fertilty patients

Purpose

To review options for ovarian stimulation before oocyte collection for fertility preservation for women with cancer or related diseases who require potentially sterilizing chemo- or radiotherapy.

Methods

Narrative review of current practice.

Results

Vitrification of oocytes and embryos has improved chances of pregnancy for this group of patients in recent years, increasing the uptake of fertility preservation before cancer treatment substantially. Strategies for ovarian stimulation for such patients should optimize oocyte yield whilst avoiding risk of ovarian hyperstimulation.

Conclusions

Best practice in ovarian stimulation can deliver good numbers of oocytes or embryos for cryopreservation with minimal risk of ovarian hyperstimulation for women under 36 years of age. Results are less encouraging for older patients.     

Ovulation induction in the gynecological cancer patient

Malignancy is a serious disease that can lead to serious morbidity and mortality. However, the survival rates for women with cancers have increased significantly during the past decades, reflecting improved diagnosis and treatment. With the increased survival in young women with cancer, more attention is being paid to preservation of fertility, which is potentially jeopardized by chemotherapy and radiation therapy, aiming to limit the devastating sequelae of this serious illness by providing these young women with a hope for motherhood. In vitro fertilization with oocyte or embryo cryopreservation has emerged as an astounding method to preserve fertility. It entails induction of ovulation to produce oocytes, the number and quality of which are imperative factors predicting the potential efficacy of the fertility preservation procedure. The aim of this review is to discuss ovarian stimulation for fertility preservation in women with gynecological cancer.     

Assisted reproduction and breast cancer

Breast cancer is the most frequent cancer in reproductive age women. Although well known causal link between estrogen and breast cancer, the impact of ovulation induction on the risk of breast cancer still remains to be clarified. One of the recently recognized long term adverse effects of adjuvant cytotoxic chemotherapy given for breast cancer is premature ovarian failure and infertility, both of which significantly compromise the quality of life of a cancer survivor. Thanks to significant developments in assisted reproductive technologies these patients may benefit from a wide range of fertility preservation options. The most established technique is embryo cryopreservation; oocyte cryopreservation can be considered in single women; both of which require at least 2 weeks of ovarian stimulation beginning with the onset of the patient's menstrual cycle. Novel ovarian stimulation protocols using tamoxifen and letrozole can be used to increase the margin of safety in estrogen sensitive breast tumors. When there is no time available for ovulation induction, ovarian tissue can be cryopreserved for future transplantation without delay in cancer therapy. The benefit of ovarian protection by gonadotropin-releasing hormone analogues is unproven and unlikely, and thus this treatment should not be recommended as the sole method of fertility preservation.     

Fertilitätserhalt bei Krebs

Survival rates of female cancer patients are improving steadily. Clinicians are increasingly confronted with the long-term effects of chemotherapy and radiotherapy on the fertility of young women. Premature ovarian failure in women who wish to become pregnant is devastating both for the patient and her partner. In the case of predictable loss of gonadal function due to a planned cancer treatment fertility preservation options should be offered to the patient. Current methods of fertility preservation include conventional reproductive techniques as well as GnRH analogue treatment, cryopreservation of oocytes and cryopreservation of ovarian tissue. Most of these techniques are still experimental and should only be decided after individual and patient-specific informed consent as well as interdisciplinary counselling.     

Technical and ethical challenges of fertility preservation in young cancer patients

As cancer treatment improves, more young men and women survive, but they suffer from infertility as a major sequel of cancer treatment. Gamete and embryo cryopreservation are the only options available to these patients for preserving their fertility. Although cryopreservation of spermatozoa and embryos are already established, oocyte banking is still experimental. The advent of testicular tissue cryopreservation and spermatogonial stem cell transplantation in men, and ovarian tissue cryopreservation and in-vitro follicular maturation in women, has started a frenzy of experiments worldwide trying to demonstrate their potential use in fertility preservation. Although major improvements have been made in tissue cryobanking in the past decade, there are still many unresolved technical issues related to these procedures. Furthermore, the intersection of cancer and fertility preservation in young patients raises ethical, legal and policy issues for oncologists and cancer survivors. Informed consent of minor patients, legal parentage and medical negligence claims are some of the potential legal challenges faced by society and healthcare providers. This review summarizes the technical and ethical challenges of gamete cryopreservation in young cancer patients.     

Ovarian tissue cryopreservation--new opportunity to preserve fertility in female cancer patients

INTRODUCTION: Malignant disease and the therapy are major factors that may result in complete loss of fertility. There are several strategies for fertility preservation in fertile women faced with cancer. A modern and potentially effective method of reproductive function protection is ovarian tissue cryopreservation. MATERIALS AND METHODS: This paper summarizes the medical and scientific knowledge in this interesting multidisciplinary medical field. Furthermore, the authors' own experience with this novel and interesting method of ovarian tissue protection is presented. Ovarian tissue was obtained during laparoscopic surgery in five nuliparous women (aged 19-33) with a diagnosis of lymphoma before chemotherapy from 2004 to 2006. After laboratory preparation, tissue was frozen by a slow cooling technique and stored in liquid nitrogen. RESULTS: In total 75 women with malignant lymphoma before chemotherapy were referred to our center for consultation--68 chose ovarian inactivation by GnRH analogues during chemotherapy, two IVF cycles with embryo or oocyte cryopreservation and five ovarian tissue cryopreservation. In these five women one to two slices of ovarian cortex from both ovaries were recovered. Totally 20 cryotubes with three pieces of tissue in each were cryopreserved. In no case was metastasis of cancer cells found by histological evaluation. CONCLUSIONS: Cryopreservation of ovarian tissue represents an effective alternative or addition to the cryopreservation of embryos or oocytes for women at risk of premature ovarian failure due to chemotherapy. Reproductive function protection requires close cooperation between oncology departments and assisted reproduction centers.     

Healthy twins delivered after oocyte cryopreservation and bilateral ovariectomy for ovarian cancer

Anti-neoplastic treatments have significantly increased the survival of cancer patients, but female patients risk premature menopause. Oocyte cryopreservation has been proposed as a fertility-saving option. This report describes the first live birth achieved with autologous cryopreserved oocytes in an ovariectomized borderline cancer patient. A patient with a borderline ovarian tumour asked for oocyte cryopreservation after a right adnexectomy. Ovulation induction resulted in the retrieval and cryopreservation of seven mature oocytes. Thirty-nine months after a left ovariectomy, the patient asked for oocyte thawing and embryo transfer. Endometrial growth was induced using hormone replacement treatment. Three of the seven cryopreserved oocytes were thawed; they survived and, after insemination, normal fertilization took place. Three embryos were transferred into the patient's uterus. A twin pregnancy was achieved with the birth of two healthy females. Oocyte cryopreservation may be a reliable option for preserving fertility in young cancer patients who risk premature menopause due to surgery, chemotherapy or radiotherapy.     

Chemotherapy and amenorrhea: risks and treatment options

PURPOSE OF REVIEW: The purpose of this study is to review the impact of chemotherapy on fertility and to update the reader on the current state of fertility preservation techniques. RECENT FINDINGS: Chemotherapy results in irreversible damage to ovarian follicles and stromal function, and alkylating agents cause the most significant damage to ovarian reserve. Options for fertility preservation range from well established techniques such as embryo cryopreservation to experimental ones such as ovarian tissue freezing. The safety and effectiveness of concomitant use of gonadotropin-releasing hormone analogues to prevent chemotherapy-induced follicle death is still debated. In-vitro maturation of germinal vesicle oocytes can be an option in patients who do not have sufficient time for ovarian stimulation. SUMMARY: The impact of chemotherapy on future fertility is much more significant than is widely believed. Because of this, young females should be counseled about fertility preservation options. Fertility preservation requires an individualized approach. If possible these patients should be encouraged to utilize the most established assisted reproductive techniques. Although success of IVF with frozen-thawed embryos now approaches that of using fresh embryos, success rates with oocyte freezing are lower but these rates are on the rise. Even though ovarian tissue cryopreservation is still an experimental technique, currently it is the only fertility preservation option in children.     

Ovarian tissue cryopreservation: therapeutic prospects and ethical reflections

Along with improved survival, methods to preserve or restore the fertility potential of young women and children treated with cytotoxic chemotherapy or pelvic radiotherapy have been developed or are in the offing. Surgery, radiotherapy and chemotherapy can all impact on the future ovarian function, but patient and disease tailored application and use of preventive measures can limit ovarian damage. When the loss of reproductive ovarian function is unavoidable, different alternatives to preserve fertility or at least to restore the procreative potential are available. Creation of embryos by IVF, oocyte donation and cryopreservation of mature or immature oocytes are potential issues, the advantages and limitations of which are discussed. Recently, ovarian tissue cryopreservation has spurred interest in the medical literature as well as in the lay press as a method for preservation and restoring fertility. Considering the available data and current state of knowledge, we want to stress that this methodology is still in an experimental phase and we would like to caution against unwarranted enthusiasm of physicians and patients. The medical information preceding the informed consent should mention the actual uncertainties of this method. Moreover, the imperative character of the offer and in particular for paediatric oncological patients, the force of the moral rules that define parental obligations towards children should not be ignored.     

Fertility preservation in female cancer survivors.

The advancement of cancer therapies over the last few decades has significantly improved long-term survival of cancer patients, especially children and adolescents. As many of the therapeutic agents used are highly cytotoxic, cancer survivors have to pay the price of enduring various immediate and long-term side-effects. Unfortunately, gonadal failure and infertility are among the most common long-term side-effects, resulting in distress, lowered self-esteem and quality of life. Three modalities of fertility preservation can be offered to female patients prior to commencing their cancer treatment: embryo, oocyte and ovarian tissue cryopreservation. This paper reviews the outcomes for female patients who underwent fertility preservation in University College Hospital between 1995 and 2005, and post-therapeutic use of their frozen specimens. In addition, the effects of cytotoxic agents on fertility and ovarian function, and the range of fertility preservation available for female cancer sufferers are also discussed.     

Preservation of female fertility during cancer treatment

Improvements in the success of cancer treatments have resulted in increased awareness of the long-term effects of treatment, of which gonadal failure is the most significant. Thus, preservation of fertility potential has become a major goal and could be realized by preventing ovarian toxicity or by cryopreservation of reproductive cells/tissues. This review aimed to critically discuss the current protocols for the management of chemotherapy-inducced/radiotherapy-induced premature ovarian failure (POF). A medical approach using the gonadotropin-releasing hormone analog (GnRHa) may act to protect the gonads during radiation and/or chemotherapy by preferentially steering cells into cell cycle arrest with a decline in responsibility to the chemotherapeutic agents. Ovarian protection by GnRHa cotreatment against chemotherapy can enable the preservation of future fertility in survivors and prevent the bone demineralization and osteoporosis associated with hypestrogenism and POF. In vitro fertilization of retrieved oocytes could enable embryo freezing in some patients. Embryo cryopreservation is considered standard practice and widely available, but may seldom be used because of a lack of a male partner, the need to postpone cancer therapy for a few weeks and the possibility that an estrogen rise may be undesirable in sensitive cancer patients. Improvement in oocyte cryopreservation may offer additional possibilities; the prolonged culture of primordial and primary follicles in vitro is still unfeasible. Currently, the cryopreservation of ovarian cortex, which hosts thousands of immature follicles, is an investigational method, but has the advantage of requiring neither a sperm donor nor ovarian stimulation. Fertility preservation is often possible in women undergoing cancer treatment. To preserve the full range of options, fertility preservation procedures should be considered as early as possible during therapy planning. (Reprod Med Biol 2008; 7 : 17–27)