Fertility preservation medicine: A new field in the care of young cancer survivors

Treatment modalities for numerous oncological and non‐oncological conditions result in gonadal insufficiency and infertility. Furthermore, pelvic‐abdominal radiation may result in uterine damage resulting in poor reproductive outcomes such as preterm birth, low birth weight, and spontaneous abortion in adult survivors of childhood cancers. In response to the recognition of the impact of cancer treatments on fertility, several fertility preservation techniques have been developed. In prepubertal children, fertility preservation options are usually limited to ovarian cryopreservation because of sexual immaturity, but oocyte freezing can be performed in adolescent children. Two prospective randomized studies showed no benefit of gonadal suppression with GnRH analogs to preserve gonadal function and thus this treatment should not be recommended. For adult survivors of childhood cancer who experienced reproductive failure, third party reproduction techniques are highly successful. Pediatr Blood Cancer 2009;53:267–273. © 2009 Wiley‐Liss, Inc.     

Ovarian tissue cryopreservation: a practical option?

Strategies to preserve fertility in young women undergoing potentially curative chemotherapy for malignant disease have been extremely limited. This limitation stems from the complex physiology of the human oocyte and the difficulties encountered in attempting to cryopreserve both developing and mature oocytes in sufficient quantities. Although in vitro fertilization and embryo cryopreservation can be used in those young women with a partner, this technique is unsuitable for the vast majority of patients and offers only a small chance of a pregnancy. Advances in cryobiology coupled with encouraging results in laboratory animals have prompted research into the storage of ovarian cortical tissue, which in young women is rich in primordial follicles. This tissue can be grafted back into the host, theoretically restoring the possibility of normal fertility. Primordial follicles contain oocytes at their least differentiated stage and appear to be relatively resistant to the combined insults of cryopreservation and the subsequent grafting procedure. Interest in this technique has been fuelled by its successful application in large domestic animals, such that ovarian tissue banking is being rapidly adopted into clinical practice before there is any hard evidence of its efficacy in humans.     

Ovarian tissue cryopreservation: a practical option?

Strategies to preserve fertility in young women undergoing potentially curative chemotherapy for malignant disease have been extremely limited. This limitation stems from the complex physiology of the human oocyte and the difficulties encountered in attempting to cryopreserve both developing and mature oocytes in sufficient quantities. Although in vitro fertilization and embryo cryopreservation can be used in those young women with a partner, this technique is unsuitable for the vast majority of patients and offers only a small chance of a pregnancy. Advances in cryobiology coupled with encouraging results in laboratory animals have prompted research into the storage of ovarian cortical tissue, which in young women is rich in primordial follicles. This tissue can be grafted back into the host, theoretically restoring the possibility of normal fertility. Primordial follicles contain oocytes at their least differentiated stage and appear to be relatively resistant to the combined insults of cryopreservation and the subsequent grafting procedure. Interest in this technique has been fuelled by its successful application in large domestic animals, such that ovarian tissue banking is being rapidly adopted into clinical practice before there is any hard evidence of its efficacy in humans.     

Fertility preservation in children and adolescents with cancer

With excellent survival rates for individuals diagnosed with cancer during childhood or adolescence an awareness of quality of life, including fertility preservation is essential. Chemotherapeutic regimens that include alkylating agents and radiation treatments directed at the gonads or pituitary, including total body irradiation are particularly gonadotoxic. Assessment of potential for gonadotoxicity and appropriateness of fertility preservation techniques prior to the start of cancer directed therapies in every individual pediatric patient is crucial for limiting this late effect of therapy. Sperm banking for postpubertal males prior to the initiation of gonadotoxic therapy should be considered standard of care. Postpubertal females receiving highly gonadotoxic therapy that places them at risk of acute ovarian failure should consider embryo or oocyte cryopreservation prior to the initiation of therapy. Oocyte cryopreservation, as well as cryopreservation of gonadal tissue, whether ovarian or testicular, remain experimental and as such should be offered as part of a research protocol. Females who receive treatment that deplete their ovarian reserve should be evaluated for the development of premature menopause following their treatment. Embryo or oocyte cryopreservation post therapy may offer females at risk of premature menopause the opportunity to preserve their reproductive window. Further research clarifying gonadotoxicity of contemporary treatment regimens and improving interventions to preserve fertility are necessary to prevent infertility as a long term adverse effect of cancer treatment. The establishment of programs that streamline access to current fertility preservation techniques will assist in ensuring that all eligible patients can avail themselves of current options.     

SPERM CRYOPRESERVATION PRACTICES AMONG ADOLESCENT CANCER PATIENTS AT RISK FOR INFERTILITY

To assess sperm cryopreservation among males newly diagnosed with cancer aged 13 years and older, attending oncologists assigned infertility risk (yes/no) to patients and reported whether their patients engaged in sperm cryopreservation. Only 28.1% of informed at-risk patients banked sperm. Utilization of sperm banking was significantly associated with a diagnosis of central nervous system (CNS) malignancy or non-CNS solid tumor diagnosis, higher socioeconomic status, and not being a member of an Evangelical religious group. These results suggest that sperm banking is underutilized among adolescent males newly diagnosed with cancer, and that strategies to increase the engagement in this fertility preservation method are needed.     

Sperm banking in adolescent cancer patients.

BACKGROUND: Semen cryopreservation is a widely available method of maintaining fertility in male cancer patients. However this facility is not always used. AIMS: To identify the barriers to successful sperm banking in a group of adolescent and young adult patients. METHODS: Questionnaires were administered to 55 patients aged 13-21 years who had received potentially gonadotoxic therapy between 1997 and 2001 and had been offered sperm banking. RESULTS: Forty five questionnaires were completed; 67% of respondents were able to bank sperm. Those who had been unsuccessful were younger and described higher levels of anxiety at diagnosis and greater difficulty in talking about fertility. They also described less understanding of sperm banking at the time of diagnosis. CONCLUSION: Most adolescent cancer patients who have been offered fertility preservation are able to bank sperm. Younger patients may be helped by the provision of high quality information and more open discussion of the technique.     

Testicular stem cells for fertility preservation: Preclinical studies on male germ cell transplantation and testicular grafting

Spermatogonial stem cells open novel strategies for preservation of testicular tissue and fertility preservation in boys and men exposed to gonadotoxic therapies. This review provides an update on the physiology of spermatogonial stem cells in rodent and primate testes. Species‐specific differences must be considered when new technologies on testicular stem cells are considered. Germ cell transplantation is presented as one novel and promising strategy. Whereas this technique has become an important research tool in rodents, a clinical application must still be regarded as experimental and many aspects of the procedure need to be optimized prior to a safe and efficient clinical application in men. Testicular grafting opens another exciting strategy for fertility preservation. Autologous and xenologous transfer of immature tissue revealed a high regenerative potential of immature testicular tissue. Grafting was applied in rodents and primates and resulted in the generation of sperm. Further research is needed before an application in humans can be considered safe and efficient. Despite the current limitations in regard to the generation of sperm from cryopreserved male germline cells and tissues, protocols for cryopreservation of testicular tissue are available and reveal a promising outcome. Since future improvements of germ cell transplantation and grafting approaches can be assumed, bioptic retrieval and cryopreservation of testicular tissue fragments should be performed in oncological patients at high risk of fertility loss since this is their only option to maintain their fertility potential. Pediatr Blood Cancer 2009;53:274–280. © 2009 Wiley‐Liss, Inc.     

Sperm banking in adolescent cancer patients

Background

Semen cryopreservation is a widely available method of maintaining fertility in male cancer patients. However this facility is not always used.

Aims

To identify the barriers to successful sperm banking in a group of adolescent and young adult patients.

Methods

Questionnaires were administered to 55 patients aged 13–21 years who had received potentially gonadotoxic therapy between 1997 and 2001 and had been offered sperm banking.

Results

Forty five questionnaires were completed; 67% of respondents were able to bank sperm. Those who had been unsuccessful were younger and described higher levels of anxiety at diagnosis and greater difficulty in talking about fertility. They also described less understanding of sperm banking at the time of diagnosis.

Conclusion

Most adolescent cancer patients who have been offered fertility preservation are able to bank sperm. Younger patients may be helped by the provision of high quality information and more open discussion of the technique.     

Reproductive technologies 1998: options available for the cancer patient.

Recent advances in the field of reproduction have potentially opened opportunities for the preservation of the reproductive potential of young cancer patients with good long-term prognosis for survival. In the postpubertal male, cryopreservation of ejaculated sperm is both feasible and potentially successful. Semen parameters at the time of procurement are of minor significance; intracytoplasmic sperm injection (ICSI) can bypass sperm concentration and motility problems and can lead to successful fertilization. For the prepubertal male there are no clinically applicable options insofar as extraction and cryopreservation of postmeiotic sperm cells (mature spermatozoa or round spermatids) is not feasible. To date, efforts for culture of testicular tissue and in vitro maturation of male germ cells have not been successful. In both pre- and postpubertal females, cryopreservation of ovarian cortical tissue or enzymatically extracted follicles and the in vitro maturation of preantral follicles are of potential clinical use, but, to date, these approaches have been successful only in laboratory animals. An additional option available to the postpubertal female is the stimulation of ovaries with exogenous gonadotropins and retrieval of mature oocytes for cryopreservation. The recent application of ICSI in previously cryopreserved human mature oocytes has improved fertilization rates and has resulted in live births. Unfortunately, a shortcoming of this approach is the limited number of oocytes that can be harvested after stimulation of the ovaries. Further, all these approaches potentially harbor the risk of the cryopreservation of malignant cells with their subsequent reintroduction in the patient at a later date. This is a more realistic concern for patients suffering from hematologic or gonadal tumors. Finally, even though cryopreservation of embryos has been successfully used for many years, this option is not available to the pediatric and adolescent patient. It should not be forgotten that, even if the patients' own gametes are not available in the future, donor sperm and eggs provide the option for offspring and can give the opportunity to the females to carry a pregnancy as long as their uterus has not been affected by the cancer treatment. Given the rapid progress we are witnessing in the field of reproductive medicine, it is probable that in the very near future most of the options described and newer ones will be clinically available.     

Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer

Increasingly young people survive cancer in childhood and as a result complications of its treatment are becoming more common and important. Premature ovarian failure is recognized as a complication of radiotherapy to a field that includes the pelvis and alkylating‐agent‐based chemotherapy. Young pre‐pubertal girls are not protected from the effects of gonadal toxic therapy. A young woman, successfully treated for cancer during childhood, may experience regular periods in the presence of a significantly reduced ovarian reserve. There is, however, no reliable measure of ovarian reserve available for the individual woman. Assessment of ovarian function relies on the use of surrogate markers such as follicle stimulating hormone, inhibin‐B, and anti‐mullerian hormone as well as ultrasound assessment of ovarian volume and antral follicle count. We discuss the physiology of normal ovarian function, the effects of cancer treatments on ovarian function and the techniques for evaluation of ovarian reserve in survivors of childhood cancer. Pediatr Blood Cancer 2009;53:296–302. © 2009 Wiley‐Liss, Inc.     

Ovarian tissue cryostorage and grafting: an option to preserve fertility in pediatric patients with malignancies

Fertility preservation in childhood cancer has become an important area of investigation due to increasing survival rates after cancer therapy. For these patients with an increased risk of infertility and premature ovarian failure, cryopreservation of ovarian tissue is a promising tool to preserve at least part of the reproductive potential. In recent years significant improvements have been achieved in this area, and 2 live births after autografting of frozen-thawed ovarian tissue have been reported. However, further research is needed to assess the clinical effectiveness of ovarian cryopreservation, to optimize the technique, and to limit the risk of reintroducing cancer cells in the patient with the graft.     

Anthropomorphic measurements and event-free survival in patients with favorable histology Wilms tumor: a report from the Children's Oncology Group

There are several methods of fertility preservation available for female patients facing infertility following gonadotoxic treatment of cancer or systemic disease. Embryos, oocytes or ovarian tissue can be cryopreserved and stored until the time when the patient is cured of her main disease and is expecting parenthood. The individual's choice depends on the nature and stage of the main disease, expected treatment, their condition, and age and existence of the partner. It is important to inform all such women about the options, and together with them, choose the most appropriate ones. It is often possible to save ovarian tissue even though the first chemotherapy courses have been undergone, but many more follicles can be stored before cancer treatment. Pediatr Blood Cancer 2009;53:254–260. © 2009 Wiley‐Liss, Inc.     

OVARIAN TISSUE CRYOSTORAGE AND GRAFTING: An Option to Preserve Fertility in Pediatric Patients with Malignancies

Fertility preservation in childhood cancer has become an important area of investigation due to increasing survival rates after cancer therapy. For these patients with an increased risk of infertility and premature ovarian failure, cryopreservation of ovarian tissue is a promising tool to preserve at least part of the reproductive potential. In recent years significant improvements have been achieved in this area, and 2 live births after autografting of frozen–thawed ovarian tissue have been reported. However, further research is needed to assess the clinical effectiveness of ovarian cryopreservation, to optimize the technique, and to limit the risk of reintroducing cancer cells in the patient with the graft.     

Feasibility of ovarian tissue cryopreservation for prepubertal females with cancer

BACKGROUND: Loss of fertility is one of the long-term adverse effects of high-dose chemotherapy or total body irradiation for cancer, even in children. Ovarian tissue cryopreservation (OTC) may make it possible for survivors of childhood cancer to have children. We evaluated the feasibility of this technique for prepubertal girls. METHODS: Between September 2000 and February 2005, 49 prepubertal girls were referred to the Reproductive Biology Unit for OTC before sterilizing treatment. RESULTS: One ovary each was collected from 47 patients, by laparoscopy in 24 patients and laporotomy in the others. In 16 cases, the ovary was harvested during laparotomy to resect a residual abdominal tumor. No complications occurred after operations. Ovarian tissue was frozen by a slow-cooling protocol, using DMSO and sucrose as cryoprotectants. An mean of 17.6 +/- 6.5 ovarian tissue fragments was cryopreserved per patient. Follicle concentration was evaluated histologically for 46 patients and a strong correlation was found between age and follicular density. None of the cases had visible ovarian tumor components. Ovarian cryopreservation was not carried out for two patients. CONCLUSION: The cryopreservation of ovarian tissue could be systematically offered even to prepubertal girls at risk of sterility due to gonadotoxic treatment.     

Preservation of fertility in children treated for cancer.

As treatment for childhood cancer has become increasingly successful, adverse effects on reproductive function are assuming greater importance. Preservation of fertility before treatment must be considered in all young patients at high risk of infertility, and provision of such services requires collaboration between oncology centres and assisted conception units. The UK Children's Cancer Study Group is planning to audit current management of preservation of reproductive function in young patients with cancer, and the British Fertility Society is preparing a voluntary code of best practice to guide and inform clinicians and scientists. Limitation of radiation exposure by shielding of the testes and ovaries should be practiced where possible and sperm banking should be offered to all sexually mature boys at risk of infertility. The rapidly advancing experimental techniques for harvesting of gonadal tissue must be considered and embarked on without unrealistic expectations, although future utilisation of the tissue is unlikely to be realised until the next decade.     

Preservation of fertility in children treated for cancer

As treatment for childhood cancer has become increasingly successful, adverse effects on reproductive function are assuming greater importance. Preservation of fertility before treatment must be considered in all young patients at high risk of infertility, and provision of such services requires collaboration between oncology centres and assisted conception units. The UK Children's Cancer Study Group is planning to audit current management of preservation of reproductive function in young patients with cancer, and the British Fertility Society is preparing a voluntary code of best practice to guide and inform clinicians and scientists. Limitation of radiation exposure by shielding of the testes and ovaries should be practiced where possible and sperm banking should be offered to all sexually mature boys at risk of infertility. The rapidly advancing experimental techniques for harvesting of gonadal tissue must be considered and embarked on without unrealistic expectations, although future utilisation of the tissue is unlikely to be realised until the next decade.     

Cryopreservation of semen from pubertal boys with cancer

BACKGROUND: The possibility of cryopreservation of semen from adolescents has until now received only little attention. Therefore, we have investigated the possibility of cryopreservation of semen in adolescent boys with cancer. PROCEDURE: Forty-five boys, aged 13-18 years, admitted because of cancer during the period January 1, 1995 to July 31, 1998 were eligible. Semen was obtained after masturbation in the majority of the cases. In three boys, semen was preserved after penile vibration or electroejaculation in general anaesthesia. The semen samples were analysed for concentration, motility, and morphology according to the WHO guidelines. The sample was transferred into straws prior to cryopreservation at 196 degrees C in liquid nitrogen. RESULTS: Twenty-one boys delivered a semen sample for cryopreservation. Four boys were offered and accepted sperm banking but were not able to produce a sample. In 20 cases time did not allow an attempt of sperm banking, the boy was not assessed to be mature enough to deliver a semen sample, or the procedure was not accepted. The boys delivered 1-3 samples, and the total number of spermatozoa ranged from 0-210 millions. Median percentage of motile sperm was 50% (range 9-86%). Semen quality improved with age; however, a 13- year- old boy produced 75 million spermatozoa with 38% motile cells. CONCLUSIONS: Pubertal maturation should be assessed in all boys admitted for cancer, and the possibility of sperm banking should be discussed with the patient and his parents.     

Attitudes and practices of oncologists toward fertility preservation

Cancer is a life-threatening diagnosis. Fortunately, life-saving treatments are available to increase the chance of survival in many patients. Yet, many of these treatments are damaging to the reproductive organs and the patients' fertility. A cross-sectional study addressing the knowledge and practices of oncologists toward fertility preservation for male and female patients with cancer was conducted in Saudi Arabia. In 3 different regions of the country, oncologists were invited to participate in the study, through a self-administered questionnaire which was handed to them inquiring about their knowledge, attitude, and referral practices for sperm cryopreservation. Only one-half knew about intracytoplasmic sperm injection, oncologists rated their perception of the importance of cryopreservation as 7.8 ± 1.8. Their referral practice was very poor; less than 20% refer their patients to a specialist. Factors that were considered important to start discussion of cryopreservation were type of cancer, age of patient, number of children, marital status, and cost. Religion was not deemed as important as was anticipated. With regards to female fertility preservation, oncologists showed a positive attitude as revealed from their positive perception, however, their referral practices was very poor. Several gaps were present in the knowledge of oncologists, which could influence their attitude and in turn was reflected on their poor practice. Future training session should be organized to the oncologists for increasing their knowledge and enhancing their attitude.     

Should ovarian cryopreservation be offered to girls with cancer

Current therapy of childhood cancer makes long-term survival a realistic outcome for most patients. However, some treatment regimens entail a significant risk of infertility. No established method for preservation of female fertility is currently available. Ovarian cryopreservation is an experimental technology that is being offered with increasing frequency to women undergoing cancer therapy. It has not yet been reported in children and adolescent girls. The aim of this review is to stimulate discussion on the possibility of performing ovarian cryopreservation in pre-menarcheal girls in advance of therapies that may induce ovarian failure. We present a multi-disciplinary discussion of the risks and benefits associated with the procedure and propose guidelines for its implementation. We propose that all girls about to receive treatment that has a high risk for infertility be offered consultation about the possibility of ovarian cryopreservation.     

Massive ovarian oedema: An unusual abdominal mass in infancy

We describe a 13‐month‐old female who presented with vaginal bleeding, breast and pubic hair development and an abdominal mass. She underwent emergency laparotomy and left‐sided salpingoopherectomy. Histological examination of the resected ovary revealed massive ovarian oedema, a rare non‐neoplastic enlargement of the ovary. Consideration of this diagnosis in patients with an abdominal mass and endocrine disturbance may allow conservative surgery and preservation of fertility. Pediatr Blood Cancer 2009;53:217–219. © 2009 Wiley‐Liss, Inc.