Preserving female fertility following cancer treatment: Current options and future possibilities

Children and women of reproductive age are increasingly surviving cancer diagnoses, and therefore long‐term quality‐of‐life issues are of greater importance at the time of diagnosis. Cancer therapies including radiation and chemotherapy can be detrimental to fertility, and therefore many patients are motivated to preserve fertility prior to cancer treatment. The only highly successful method in preserving fertility to date is embryo cryopreservation, which may not be appropriate for some patients due to age, delay in treatment, cancer type and stage, as well as availability of an acceptable sperm donor. Alternative methods including oocyte cryopreservation and ovarian tissue banking may also preserve fertility while providing additional flexibility to patients. In vitro ovarian follicle maturation following tissue banking is one potential approach that would not require a delay in cancer therapy for ovarian stimulation, would not require an immediate sperm donor, and does not carry the risk of reintroducing malignant cells following tissue transplantation. In vitro follicle culture systems have resulted in successful live births in the mouse. However, many challenges must be addressed in translating the system to the human. This review summarizes current approaches to fertility preservation and discusses recent developments and future challenges in developing a human in vitro follicle culture system. Pediatr Blood Cancer 2009;53:289–295. © 2009 Wiley‐Liss, Inc.     

Educational paper

Over the past several decades, pediatric oncologists have seen the growth in the number of patients surviving their cancer. This is in large part due to the use of multimodal therapy including chemotherapy, surgery, and radiotherapy. As the number of survivors of pediatric cancer continues to grow, however, we need to begin to focus on improving the quality of the lives that are being saved. Unfortunately, many regimens used today to cure pediatric cancer patients are gonadotoxic. Therefore, many of our survivors must contend with infertility. It is critical that pediatric oncologists consider the likelihood of gonadotoxicity prior to beginning therapy in this patient population in order to counsel patients and their families properly in order to potentially offer fertility preservation options. Conclusion: Infertility is a critical quality of life issue for pediatric cancer survivors and their families. Fertility preservation techniques need to continue to be studied and developed in order to lessen the likelihood that future cancer survivors will be infertile. This review outlines the risk for infertility, provides an assessment of the survivors reproductive functioning, and summarizes the currently available methods of preserving fertility in pediatric cancer survivors.     

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.     

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 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.     

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.     

Impact of ovarian transposition before pelvic irradiation on ovarian function among long‐term survivors of childhood Hodgkin lymphoma: A report from the St. Jude Lifetime Cohort Study

1 Background

We reviewed the effect of ovarian transposition (OT) on ovarian function among long‐term survivors of childhood Hodgkin lymphoma (HL) treated with pelvic radiotherapy.

2 Procedure

Female participants (age 18+ years) with HL in the St. Jude Lifetime Cohort Study (SJLIFE) were clinically evaluated for premature ovarian insufficiency (POI) 10 or more years after pelvic radiotherapy. Reproductive history including age at menopause and pregnancy/live births was available on all patients.

3 Results

Of 127 eligible females with HL, 90 (80%) participated in SJLIFE, including 49 who underwent OT before pelvic radiotherapy. Median age at STLIFE evaluation was 38 years (range 25–60). In a multiple regression adjusted for age at diagnosis, pelvic radiotherapy doses > 1,500 cGy (hazard ratio [HR] = 25.2, 95% confidence interval [CI] = 3.1–207.3; P = 0.0027) and cumulative cyclophosphamide equivalent doses of alkylating agents > 12,000 mg/m² (HR = 11.2, 95% CI = 3.4–36.8; P < 0.0001) were significantly associated with POI. There was no significant association between OT and occurrence of POI (HR = 0.6, 95% CI = 0.2–1.9; P = 0.41).

4 Conclusions

OT did not appear to modify risk of POI in this historic cohort of long‐term survivors of HL treated with gonadotoxic therapy. Modern fertility preservation modalities, such as mature oocyte cryopreservation, should be offered to at‐risk patients whenever feasible.     

Survival of ovarian allografts in an experimental animal model

Transplantation of ovarian tissue is a promising strategy for fertility preservation in young cancer patients with premature ovarian failure if they have cryopreserved their own tissue before undergoing gonadotoxic treatment. However, extension of ovary donation to children and adults seeking treatment for hypogonadism is controversial unless the tissue does not provoke an immune reaction or specific tolerance can be safely and effectively achieved. The survival of heterotopic ovarian allografts was tested in a mouse model. Isografts were placed under the kidney capsule of ovariectomized animals differing at the H-2 haplotype (H-2d or H-2k). Within three wk, and in contrast to isografts, the allografts were rejected, although their survival was extended when donor and host strains shared the same haplotype (H-2k). Allograft survival was not improved if the tissue was implanted orthotopically. When monoclonal antibodies to CD4 antigens were administered at doses exceeding those effective for long-term tolerance to cardiac allografts, graft survival was prolonged in one of two strain combinations, but they failed to restore fertility. These results indicate that the ovary is not an immunologically privileged organ, as the older literature suggested, and chronic immunosuppression is likely to be required for ovarian allografts in clinical settings.     

Cryopreservation of semen from adolescent patients with malignancies

In adult oncological patients semen cryopreservation offers the possibility of preserving fertility prior to aggressive therapy that may lead to infertility. The cryopreserved semen can later be used to induce pregnancies in the partner by techniques of assisted fertilization. In adolescent boys the question of fertility is often beyond consideration when the young patient's life is threatened acutely. However, improved survival rates increasingly prompt the question of quality of life after therapy, including fertility. Semen quality is known to be impaired in patients with malignancies and may be further impaired by the process of cryopreservation. Since normal values for semen in adolescents are not known and spermatogenesis may be impaired by the malignant disease, it was unclear whether semen samples from adolescents with malignancies warrant cryopreservation at all. In order to demonstrate the feasibility of semen cryopreservation in adolescent males, we compared the results from 12 pubertal boys aged 14–17 years with those from 17 young adults aged 18–20 years who had similar malignancies and, additionally, to 210 adults with malignancies (>20 years). Luteinizing hormone serum values were significantly lower in adolescents than in adult patients. Follicle stimulating hormone showed a significant increase with age. Testosterone serum levels and testicular volumes showed similar distribution patterns in adolescent and adult men. Sperm concentrations, sperm motility, and normal sperm morphology in the adolescent patients did not show significant differences compared with adults. Thus cryopreservation of semen should be considered as an option to young male patients whose cancer therapy will include potentially gonadotoxic treatment. © 1996 Wiley-Liss, Inc.     

Fertility preservation in pediatric leukemia and lymphoma: A report from the Children's Oncology Group

Certain chemotherapy agents, radiation, and surgery can all negatively impact future fertility. Consults regarding treatment-related risk for infertility and gonadal late effects of these agents should occur at the time of diagnosis as well as during survivorship. Counseling on fertility risk has traditionally varied significantly across providers and institutions. We aim to provide a guide to standardize the assignment of gonadotoxic risk, which can be used in counseling patients both at the time of diagnosis and in survivorship. Gonadotoxic therapies were abstracted from 26 frontline Children's Oncology Group (COG) phase III protocols for leukemia/lymphoma, in use from 2000–2022. A stratification system based on gonadotoxic therapies, sex, and pubertal status was used to assign treatments into minimal, significant, and high level of increased risk for gonadal dysfunction/infertility. Risk levels were assigned to protocols and different treatment arms to aid oncologists and survivor care providers in counseling patients regarding treatment-related gonadotoxicity. Males were most commonly at high risk, with at least one high-risk arm in 14/26 protocols (54%), followed by pubertal females (23% of protocols) and prepubertal females (15% of protocols). All patients who received direct gonadal radiation or hematopoietic stem cell transplant (HSCT) were considered at high risk. Partnering with patients and their oncology/survivorship team is imperative for effective fertility counseling both prior to and post treatment, and this comprehensive guide can be used as a tool to standardize and improve reproductive health counseling in patients undergoing COG-based leukemia/lymphoma care.     

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.     

Gonadal function and pubertal development after treatment of a childhood malignancy

As survival rates for childhood cancer have improved, the importance of assessing gonadal dysfunction caused by alkylating agents and radiotherapy in children treated for cancer has increased. Infertility is the major long-term side effect of chemotherapy (CT) in males, whereas Leydig cell function is less affected. Our studies confirm that prepuberty does not protect the male gonad from the late effects of CT and that protocols less gonadal-lesive (such as ABVD regimens) should be preferred. Ovaries are less affected, but early depletion of follicles and premature menopause may occur. High-dose busulfan conditioning regimens cause ovarian failure in young females. The role of gonadal irradiation is discussed: high dosages (>2000 cGy) provoke sterility, impaired testosterone secretion in males and estradiol release in females. High dosage hypothalamic-pituitary irradiation causes delayed puberty and hypogonadism in males and females, whereas lower dosages may be associated with early puberty, particularly in females.     

Ovarian repositioning in pediatric cancer patients: Flexible techniques accommodate pelvic radiation fields

Treatments for childhood cancer and consequent long-term survival rates continue to improve. As the success of these therapies advances, premature ovarian failure and sterility have become an increasingly evident long-term morbidity. Abdominal and pelvic radiation have been specifically shown to induce early menopause and decreased fertility. In order to minimize radiation injury, we utilized novel techniques to reposition ovaries in two girls with pelvic tumors prior to initiation of pelvic radiation. One girl with a sacral Ewing sarcoma underwent laparoscopic anterior suspension of the ovaries, using a simple and easily reversible technique. The second patient, who underwent hysterectomy for a recurrent uterine rhabdomyosarcoma, underwent widely lateral and cephalad repositioning of the ovaries. Both procedures were well tolerated, with no significant morbidity. In both cases the ovaries were moved well beyond the planned radiation field. We propose that open or laparoscopic ovarian repositioning in children is a simple, flexible, and reversible option to reduce radiation injury to the ovaries in pediatric cancer patients.     

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.     

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.     

Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study

Background

Gonadal function decades after treatment for childhood lymphoma (CL) is not well described. This cross‐sectional study had two aims: (1) describe long‐term gonadal function and fertility in childhood lymphoma survivors (CLSs), and (2) explore anti‐Mullerian hormone (AMH) as a measure of ovarian function in CLSs.

Procedure

Seventy‐four male and 62 female CLSs participated in a survey consisting of a questionnaire, clinical examination, and blood/semen analysis. Prior treatment was categorized according to gonadotoxicity. Hypogonadism was determined by levels of gonadal hormones based on luteinizing hormone, follicle‐stimulating hormone, testosterone (males), AMH (females <40 years), and menstrual status. Fertility was explored according to pregnancies achieved, semen analysis, and AMH.

Results

Hypogonadism was observed in 7 of 66 males (11%). Seven of 64 males (11%) were categorized as infertile. Nine of 45 females <40 years (20%) were at risk to develop premature ovarian failure (POF). Twenty of 45 females (44%) showed low‐AMH levels indicating decreased fertility. Four “critically low” females reported pregnancies within the preceding 2 years. Sixty‐four percent of the males and 93% of the females attempting parenthood had been successful (P = 0.01). Hypogonadism and low‐AMH were related to treatment burden.

Conclusion

Twenty years after treatment of CL, female CLSs' attempts of pregnancy initiation are mostly successful, while males seem at higher risk of infertility. Hypogonadism is a problem in 10% of the male CLSs. Based on AMH levels, POF is a risk in 20% of the female CLSs. The clinical significance of AMH reflecting true probability of fertility needs further research in cancer survivors. Pediatr Blood Cancer 2012;59:271–277. © 2011 Wiley Periodicals, Inc.     

Orthotopic ovarian transplant--review and three surgical techniques

Transplantation of organs is a rapidly expanding faculty of medicine. While the solid organ transplantation has grown by leaps and bounds, ovarian transplantation is still in its infancy. Although recent interest has been generated for preservation of fertility in cancer therapy patients, other indications have emerged. Ovarian dysgenesis with missing normal ovarian complement and premature ovarian failure has come in the forefront. Three cases of orthotopic ovarian transplant with different surgical techniques have been described along with a brief overview.     

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.