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.     

Fertility preservation for medical reasons in girls and women: British fertility society policy and practice guideline

Fertility preservation in the female poses several challenges due to the invasive nature of the techniques available to achieve it. The guideline aims to bring together the evidence available for the measures for fertility preservation and their outcome. The guideline addresses fertility preservation for medical reasons and includes both oncological and non-oncological causes. The techniques that the guideline considers are: (i) embryo and oocyte cryopreservation; (ii) ovarian tissue cryopreservation; (iii) GnRH agonist suppression and (iv) ovarian transposition. Although ovarian tissue cryopreservation is still considered experimental, the availability of this technique is gaining momentum as more live births from auto-transplanted tissue are reported. The guideline also highlights use of current treatment modalities for benign and malignant conditions that have a better fertility sparing profile. The guideline recommends a multidisciplinary approach in counselling women and girls about the risk to their fertility and available techniques. The role of psychological support in assisting women and girls with decision-making is highlighted. The guideline also highlights the risks associated with these techniques. Women need to be medically fit to undergo invasive procedures. Fertility preservation techniques are appropriate when treatment has curative intent. Fertility preservation is a subject of on-going research on outcomes of different techniques and at the time of publication, studies are still likely to emerge adding to the available literature.     

Importance of ovarian tissue cryopreservation in fertility preservation and anti-aging treatment

Abstract

Various oncological and non-oncological diseases, as well as their treatments, can cause premature ovarian insufficiency and reduce a woman’s reproductive potential. Fertility preservation is, therefore, becoming an emerging field of reproductive medicine allowing these patients to have their own biological children. The aim of this review is to analyze the importance of ovarian tissue cryopreservation as a fertility preservation method as well as its new role as a hormone replacement treatment. Although ovarian tissue cryopreservation is currently regarded as an experimental procedure, it is rapidly advancing and may become an established fertility preservation method in the near future. This method does not require ovarian stimulation or a subsequent delay in the initiation of cancer treatment. Furthermore, orthotopic ovarian tissue transplantation offers the unique opportunity of spontaneous conception. Due to the restoration of endocrine function following the procedure, ovarian tissue cryopreservation may also be used as tissue hormone replacement therapy in cases of premature ovarian insufficiency, to postpone menopause and prevent its troublesome symptoms and diseases. Even though the role of ovarian tissue cryopreservation as a new anti-aging treatment modality is quite promising, the safety and efficacy of this approach should be investigated in clinical settings.     

Cancer and fertility: strategies to preserve fertility

Fertility preservation is a key component of cancer management in young people. The Fourth Evian Annual Reproduction Workshop Meeting was held in April 2009 to discuss cancer and fertility in young adults. Specialists in oncology, assisted reproduction, embryology and clinical genetics presented published data and ongoing research on cancer and fertility, with particular focus on strategies to preserve fertility. This report is based on the expert presentations and group discussions, supplemented with publications from literature searches and the authors' knowledge. Fertility preservation should be considered for all young people undergoing potentially gonadotoxic cancer treatment. A variety of options are required to facilitate safe and effective fertility preservation for individual patients. Sperm banking is a simple and low-cost intervention. Embryo cryopreservation is the only established method of female fertility preservation. Oocyte cryopreservation offers a useful option for women without a male partner. Emergency ovarian stimulation and cryopreservation of ovarian tissue (followed by tissue transplantation or in-vitro maturation of oocytes) are experimental techniques for women who require urgent cancer treatment. Further prospective studies are required to validate cryopreservation of oocytes and ovarian tissue, in-vitro maturation of oocytes and new vitrification techniques and to identify any long-term sequelae of slow freezing of embryos.     

Fertility preservation in cancer patients

This symposium was an international gathering of clinicians and scientists working in the field of preservation of fertility for male and female cancer patients and was organized by Professor Ettore Cittadini. Two days of invited lectures covered the spectrum of options for cryopreservation of fertility, from sperm, testicular tissue and germ cells, to eggs and ovarian tissue. The UK was represented by invited talks from Daniel Brison (sperm cryopreservation), John Radford (ovarian tissue cryopreservation), Kate Hardy (in vitro culture of follicles) and David Baird (ovarian tissue cryopreservation and regrafting in sheep).     

Fertility Preservation for Prepubertal Girls: Update and Current Challenges

With increasing rates of diagnosis of childhood cancers and the evolution of more effective treatment options resulting in prolonged life spans, fertility preservation counseling is an integral component of the discussion at the time of diagnosis of childhood cancers. The primary fertility preservation option that exists for prepubertal girls is ovarian tissue cryopreservation. Although ovarian tissue cryopreservation is still considered to be experimental in nature, live births have resulted from orthotopic tissue transplantation. Fertility preservation should be offered to all prepubertal girls at high-risk for premature ovarian failure as a result of gonadotoxic treatment. Ethical and legal questions surrounding these issues must be considered as more and more pediatric patients pursue fertility preservation.     

Ovarian Tissue Transplantation: Current State and Research Advancement

During the past decade, babies born from cryopreservation and transplantation of ovarian tissue have emerged as a promising alternative to restore ovarian function and fertility in cancer patients. Despite successful results obtained with conventional freezing protocols to preserve ovarian tissue, attempt for whole ovary transplantation is still under-propelling in large animal and human studies. Patient selection to avoid reimplanting cancer cells in ovarian grafts as a prerequisite safety concern is as important as advanced transplantation technique. Multidisciplinary strategies for the combined isolation immature follicle for culture or in vitro activation of ovarian follicle with the frozen-thawed ovarian tissue raised the diversity for female fertility preservation along with the egg-embryo freezing or in vitro maturation of immature eggs. The purpose of this updated review of fertility preservation techniques is to develop a network among health care professional interested in this challenging field for those who are threatened the reproductive function.     

卵巢组织冻存移植保护女性生育力的临床应用

近年来,随着癌症诊断、治疗技术的进步和患者生存率的提高,以及国家三孩政策的放开,女性生育力保护和保存已成为国际和国内的热点。卵巢组织冻存移植技术是儿童及抗癌治疗无法延迟的育龄女性生育力保护的惟一方法。文章主要聚焦于卵巢组织冻存移植生育力保护技术的临床应用。     

Fertilit?tsprotektion bei Frauen

The improvement in survival of young cancer patients in recent years has led to an increasing interest for treatment aimed at increasing the quality of life during and after chemotherapy and radiotherapy. Thus new reports on the progress in fertility preservation techniques have led to the establishment of the German-speaking network FertiPROTEKT (http://www.fertiprotekt.eu) in 2006. Decisions on the type of fertility preservation technique offered to the patient need to be made after careful discussion by reproductive specialists and oncologists according to the cancer disease, the prognosis, the age of the patient and the available time frame until the onset of cytotoxic therapy. The different techniques, such as ovarian stimulation followed by cryopreservation of fertilized or unfertilized oocytes, cryopreservation of ovarian tissue and the use of gonadotropin-releasing hormone agonists are critically analyzed in this paper.     

Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines

In this article we review the existing fertility preservation options for women diagnosed with Turner syndrome and provide practical guidelines for the practitioner. Turner syndrome is the most common sex chromosome abnormality in women, occurring in approximately 1 in 2500 live births. Women with Turner syndrome are at extremely high risk for primary ovarian insufficiency and infertility. Although approximately 70%-80% have no spontaneous pubertal development and 90% experience primary amenorrhea, the remainder might possess a small residual of ovarian follicles at birth or early childhood. The present challenge is to identify these women as early in life as is possible, to allow them to benefit from a variety of existing fertility preservation options. To maximize the benefits of fertility preservation, all women with Turner syndrome should be evaluated by an expert as soon as possible in childhood because the vast majority will have their ovarian reserve depleted before adulthood. Cryopreservation of mature oocytes and embryos is a proven fertility preservation approach, and cryopreservation of ovarian tissue is a promising technique with a growing number of live births, but remains investigational. Oocyte cryopreservation has been performed in children with Turner syndrome as young as 13 years of age and ovarian tissue cryopreservation in affected prepubertal children. However, current efficacy of these approaches is unknown in this cohort. For those who have already lost their ovarian reserve, oocyte or embryo donation and adoption are strategies that allow fulfillment of the desire for parenting. For those with Turner syndrome-related cardiac contraindications to pregnancy, use of gestational surrogacy allows the possibility of biological parenting using their own oocytes. Alternatively, gestational surrogacy can serve to carry pregnancy resulting from the use of donor oocytes or embryos, if needed.     

恶性肿瘤治疗中卵巢冷冻和移植

恶性肿瘤发病渐趋低龄化,越来越多的年轻女性患者在经历了抗肿瘤治疗获得长期存活的同时,也无奈地失去了卵巢的内分泌功能及生育能力,严重影响其身心健康及社会角色。卵巢冷冻和移植是目前保存和恢复年轻肿瘤患者生殖功能及生育能力最有希望的选择。     

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.     

6?Jahre FertiPROTEKT

The network FertiPROTEKT was established in 2006 to combine the expertise of university clinics in Germany, Switzerland and Austria and to create a nationwide network which offers effective and low risk fertility preservation for everybody. To achieve this goal, regular workshops, cryobanks for cryopreservation of ovarian tissue and registers documenting the counselling activities and complications and several other activities have been initiated and established. The more than 3,000 cases of patient counselling, 1,000 cryopreservations of ovarian tissue, 1,000,000 visits to the FertiPROTEKT -website and detailed recommendations about fertility preservation treatments confirm the success of the network. Nevertheless, the coming years will show whether these fertility protecting activities have led to high numbers of successful pregnancies.     

The effect of cancer treatment on female fertility and strategies for preserving fertility

Aggressive chemotherapy and radiotherapy in young patients with cancer has greatly enhanced the life expectancy of these patients, but these treatments often cause infertility because of the massive destruction of the ovarian reserve resulting in premature ovarian failure (POF). This review focuses on the effect of cancer treatments on fertility and on the various surgical and assisted-reproduction innovations that are available to provide the patient with the option of future pregnancies. As the emerging discipline of fertility preservation is steadily attracting increasing interest, developments in the near future promise to be very exciting. However, in everyday routine work, better interdisciplinary cooperation between gynecological and pediatric oncologists, surgeons, immunologists and endocrinologists is necessary so that individualized options for fertility preservation can be offered in advance of surgical procedures or cancer treatments. GnRH analog treatment can preserve fertility in some patients, but not in all. At present, cryopreservation of ovarian tissue appears as a very promising method of providing the cancer patient with a realistic chance of preserving fertility—a prospect that is also extremely important to patients for psychological reasons.     

Kryokonservierung und Transplantation von Ovarialgewebe

There are relatively few effective clinical options for preserving female fertility, particularly following aggressive chemotherapy and/or radiotherapy treatment protocols. This document reviews scientific background, current technology, clinical results, and potential future applications of ovarian tissue cryopreservation and transplantation. The technology is investigational although rapidly evolving, and the list of appropriate indications may be expanded in the future. Germany stays abreast of these rapid worldwide developments by having founded the first German network of experts for fertility preservation in patients undergoing chemotherapy and/or radiotherapy.     

Treatment history and outcome of 24 deliveries worldwide after autotransplantation of cryopreserved ovarian tissue,including two new Danish deliveries years after autotransplantation

PurposeTo report another two successful pregnancies and deliveries resulting from autotransplanted cryopreserved ovarian tissue several years after the autotransplantation procedure took place. Further, to review the literature on the treatment history, number of live births and their outcome so far reported worldwide.MethodsTwo women underwent fertility preservation with cryopreservation of their ovarian tissue prior to a potentially sterilizing treatment with bone marrow transplantation. One woman suffered from paroxystic nocturnal hemoglobinuria and one woman from relapse of Hodgkin′s lymphoma. Both suffered from premature ovarian insufficiency after treatment. Because of a pregnancy wish they later had pieces of thawed cortical tissue transplanted to the remaining ovary and the anterior abdominal wall. PubMed was searched for reports of deliveries resulting from cryopreserved ovarian tissue in peer-reviewed papers.ResultsFive years after the autotransplantation the first patient became spontaneously pregnant and delivered a healthy baby boy at term. The second patient became pregnant after undergoing one cycle of in vitro fertilisation five years after the autotransplantation. She delivered a healthy baby boy at gestational week 36. Twenty healthy singletons and two sets of twins have been born according to peer-reviewed publications.ConclusionContrary to most of the published deliveries our latest two cases occurred several years after the autotransplantation procedure took place. This proves that ovarian grafts are capable of functioning for several years after the autotransplantation has occurred. Today, a total of 26 healthy children have been born as a result of cryopreservation of ovarian tissue.     

Stratégies de préservation de la fertilité chez la femme jeune atteinte de cancer du sein ou d’hémopathie maligne

The incidence of cancer in young patients as well as survival rates is steadily increasing. The question of fertility capacity is therefore of great importance regarding the quality of life after cancer. According to the ASCO recommendations, every patient should be advised about the chemotherapy-induced ovarian damage and fertility preservation possibilities. Several options can be discussed: embryo and/or oocytes freezing and ovarian tissue cryopreservation. Fertility preservation techniques are progressing rapidly but it still remains difficult to establish precise flow-charts according to age, marital status, type, dose and timing of chemotherapy.     

Efficacy of ovarian tissue cryopreservation in a major European center

Purpose

To evaluate the effect of cryopreservation and thawing of ovarian tissue from oncological patients opting for fertility preservation on ovarian tissue viability.

Methods

In this prospective cohort study, the ovarian tissue viability before and after cryopreservation and thawing was measured for 25 newly diagnosed oncological patients who had their ovarian tissue cryopreserved. Outcome measures were follicle integrity (histology), follicle viability (Calcein viability assay), steroid hormone production (estradiol and progesterone production in vitro) and overall tissue viability (glucose uptake in vitro). This study was conducted at a Cryobank for storage of ovarian tissue in a university hospital.

Results

Cryopreserved/thawed ovarian tissue showed a decreased glucose uptake when compared to tissue that had not been cryopreserved. In addition, a diminished E2 and P4 production was observed after cryopreservation and thawing, despite the fact that numbers of viable follicles as determined by the Calcein viability assay were comparable. Histological examination revealed a higher percentage of degenerated follicles after cryopreservation and thawing.

Conclusions

Ovarian tissue cryopreservation and thawing impairs the viability of ovarian tissue in oncological patients opting for fertility preservation.     

Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique

This paper presents the Danish 10-year experience (1999-2009) with cryopreservation (n=386) and autotransplantation of ovarian tissue (n=18). Before applying the technique to humans, the method was thoroughly tested and validated. The cryoprotectant solution was chosen after histological evaluation of mouse and human ovarian tissue after freezing with four different combinations of cryoprotectants. Viability was confirmed by transplantation of frozen-thawed human ovarian tissue (n=49) to oophorectomized Nude mice. Viability after transport of fresh tissue 4-5h prior to freezing had previously been validated. Overnight transport of fresh ovarian tissue prior to cryopreservation was evaluated when human ovarian tissue was kept on ice for 20h and then cryopreserved. The thawed ovarian tissue was transplanted to an oophorectomized Nude mouse and histology confirmed viability. In Denmark 12 women have received a total of 18 autotransplantations of ovarian tissue. All women resumed ovarian function and three healthy babies were born to two women. In both women, the tissue was transported on ice for 4-5h prior to cryopreservation. Ovarian tissue cryopreservation is an important method for fertility preservation; however, before applying the method clinically, each laboratory should perform thorough validation of their technique.