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.     

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.     

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 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.     

Attitudes and practices of pediatric oncology providers regarding fertility issues

PURPOSE: Given the higher survival rates of childhood cancer, health care providers must be aware of the side effects of cancer therapies to educate patients and provide appropriate interventions to reduce cancer-related morbidity. To understand the current practices and attitudes in a pediatric hematology/oncology clinic, health care providers were surveyed regarding fertility issues pertinent to their patient care. PARTICIPANTS AND INSTRUMENTS: In this study, 93.8% (30/32) health care providers in one pediatric hematology/oncology department completed a 44-item survey assessing knowledge, current practices, obstacles to current practices, perceptions of patient differences, and improvements to future practice. RESULTS: The majority of health care providers were aware of the adverse effects of alkylating agents (90.7%) and of abdominal and pelvic radiation (100.0%) on fertility. However, only half were aware of gender differences in gonadotoxicity (50.0%) or knowledgeable of current research and technology in fertility preservation (53.3%). While only 34.6% of providers currently consulted with specialists, nearly all (92.8%) indicated a desire to do so in the future, but 64.3% indicated difficulties in finding proper facilities and specialists for their patients. Almost all (96.6%) agreed that providers and patient families need more information regarding the effects of cancer therapy on fertility. CONCLUSIONS: Surveyed pediatric oncology providers considered fertility to be an important issue for childhood cancer patients and desired more resources regarding effects on fertility and fertility preservation. Greater communication needs to be established between pediatric oncology providers and specialists in reproductive medicine and endocrinology to ensure adequate professional collaboration and patient referrals.     

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.     

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.     

Attitudes regarding fertility preservation in female adolescent cancer patients

Infertility is a devastating side effect of cancer treatment. Advances in fertility research have brought new preservation techniques to the forefront for women. The implication of this research in the field of pediatric oncology has not been reported. The objective of this study was to determine whether female adolescents with a diagnosis of cancer and their parents were interested in trying to preserve fertility. We conducted a cross-sectional survey of female patients, aged 10 to 21 years, and their parents. There were 39 parent/adolescent pair responses, 3 parent-only responses, and 8 adolescent-only responses. We found that adolescents and parents had thought about the future and were interested in research treatments to help preserve fertility, but not willing to postpone cancer therapy. Achieving a state of good health was most important to the adolescent group (P<0.001). There was no statistical difference between attitudes of parents and adolescents. In summary, parents and female adolescents are interested in options to help preserve fertility during cancer treatments, but they are not willing to postpone treatment for this purpose.     

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.     

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.     

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.     

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.     

Disclosure of developmental disability: a study of paediatricians' practices

OBJECTIVE: To investigate paediatricians' practices in disclosure of disability and the influences on their practices, including attitude to people with disabilities. METHODOLOGY: Interviews were conducted with 26 paediatricians regarding their disclosure practices and their experience, training, contact with children with significant disabilities and influences on practices. Anonymous self-report questionnaires to the same group of practitioners relating to attitude to disability were also employed. RESULTS: Paediatricians' practices in the disclosure process scored relatively low on an index based upon recommended practices. No significant relationships were found between index scores and the experience or training of the paediatrician or the amount of contact of the paediatrician with children with disabilities. However, more experienced paediatricians were found to be more likely to mention the practice of informing both parents together and the presence of a support person at the time of disclosure. Paediatricians having more contact with children with disabilities were more likely to mention that they would disclose disability in a child as soon as possible. The major modifying influences on disclosure practices were reported to be the intelligence of the parents and their emotional state of at the time of disclosure. Time was the most frequently reported constraint upon disclosure practices. CONCLUSIONS: The low 'disclosure practice index' scores in this study are not necessarily an indication that practices are poor, as there are challenges to the validity of the advocated practices. There were few significant associations found between the practices of paediatricians in disclosure and their experience, training, contact with children with disabilities and attitude to people with disabilities.     

Immunisation practices of paediatric oncologists: an Australasian survey

AIM: The aim of this survey was to identify the current practices of paediatric oncologists in Australia and New Zealand regarding the immunisation of children treated for cancer. METHODS: The survey was a nine-part questionnaire of current immunisation practices emailed to all paediatric oncologists practising in Australia (nine centres) and New Zealand (three centres) in June 2006. RESULTS: Overall response rate was 82% (37 of 45 oncologists). Ninety-four per cent of respondents would recommend commencing 'booster' vaccinations at 6 months post completion of chemotherapy, in keeping with the current guidelines. Seventy-four per cent would recommend varicella vaccination. Intensity of the chemotherapy treatment was felt to be important, with 97% recommending re-immunising after a high-intensity regimen and only 48% after a lower-intensity regimen. Sixty-nine per cent stated they would recommend yearly influenza vaccinations for their patients. CONCLUSION: This survey highlights the variability of practice in Australasia; for example, nearly one-third do not recommend yearly influenza vaccination for their patients. The level of chemotherapy intensity was an important factor for paediatric oncologists in determining whether 'booster' vaccinations were recommended. This is an important cancer survivorship issue and review of the evidence-base and implementation of these guidelines is required.     

改良快速冷冻载体冻融人类稀少精子的实验研究

目的探讨人类稀少精子冷冻改良快速冷冻载体的实验研究,为重度少弱精子症患者的精子冷冻保存提供参考。方法2018年12月至2019年8月,在联勤保障部队第九〇〇医院生殖中心就诊的男性不育症患者:根据精液质量分为正常精液组和少弱精液组,每个实验样本选取3份精液分别进行充分混合,将混合精液稀释至浓度为(1~2)×10~6/ml,实验共计选取81份正常精液标本混匀稀释形成27个正常精液样本,选取54份少弱精液标本混匀稀释形成18个少弱精子样本。根据不同的冷冻载体各分3组进行精子冷冻:薄片精子冷冻管组(A组),麦管微量体积冷冻组(B组),改良快速冷冻载体组(C组),均采用商品化精子冷冻试剂1∶1混匀,熏蒸法后快速冷冻。比较3种载体冷冻复苏后,精子的活动力、存活率、DNA碎片指数和正常形态变化、精子顶体酶活性等指标变化,以评估改良快速冷冻载体的冷冻效率及安全性。统计学方法采用t检验、ANOVA分析、LSD多重比较。结果正常精液组的3种冷冻方法都会造成精子质量下降。正常精液组的C组的复苏后精子活动力、存活率均高于A组和B组,差异有统计学意义(P<0.05)。正常精液组:C组复苏精子DNA碎片指数略低于A和B组,但差异无统计学意义(P>0.05);A、B、C 3组复苏后精子正常形态率均低于冷冻前,差异有统计学意义(P<0.05)。少弱精液组:A、B两组复苏后精子DNA碎片指数均高于冷冻前,差异有统计学意义(P<0.01);C组精子DNA碎片指数高于冷冻前,但差异无统计学意义(P=0.068),C组复苏精子DNA碎片指数略低于A和B组,但差异无统计学意义(P>0.05),A、B、C 3组冷冻精子复苏后正常形态率均低于冷冻前,差异无统计学意义(P>0.05)。正常精液组:冷冻前精子顶体酶活性为(123.6±12.8)IU/10~6个精子,复苏后A、B、C 3组顶体酶活性均有下降,分别为(74.7±15.6)、(84.7±13.5)、(91.2±16.2)IU/10~6个精子,差异有统计学意义(F=37.896,P<0.001),从对于精子顶体影响看,B、C组优于A组,差异有统计学意义(P=0.043、P=0.001)。结论改良快速冷冻载体对于稀少精子冷冻保存有一定优势,值得进一步探讨研究。     

<Emphasis Type="Italic">Priority Mental Health Disorders</Emphasis> of Children and Adolescents in Primary-care Pediatric Settings in India 2: Diagnosis,Pharmacological Treatment and Referral

The advent of pediatric psychopharmacology has enormously improved psychiatric care of children and adolescents. Nonetheless, our practice of diagnosis, treatment and referral in primary-care pediatric settings is not optimum as current evidence based knowledge is not regularly applied in the actual clinical circumstances. To help primary-care pediatricians minimise this in research-clinical practice, pharmacological treatment and referral in their clinical practice, they need to follow a two-tier diagnostic and multi axial treatment approach. The two-tier diagnostic approach of using a screening measure followed by confirmation of the screen positive cases with reference standard clinical criterion, improves the sensitivity and specificity. The multiaxial treatment has the advantage of offering a holistic approach to the intervention and improve prognosis from the interacting axes. The primary-care physician should be aware of the medications of choice for the Priority Mental Health Disorders and their drug interactions. Finally, referral of cases with atypical presentations, multiple comorbidities and poor response to the first-line of treatment needs referral to the next tier in the system.     

Priority mental health disorders of children and adolescents in primary-care pediatric settings in India 2: diagnosis, pharmacological treatment and referral

The advent of pediatric psychopharmacology has enormously improved psychiatric care of children and adolescents. Nonetheless, our practice of diagnosis, treatment and referral in primary-care pediatric settings is not optimum as current evidence based knowledge is not regularly applied in the actual clinical circumstances. To help primary-care pediatricians minimise this in research-clinical practice, pharmacological treatment and referral in their clinical practice, they need to follow a two-tier diagnostic and multi axial treatment approach. The two-tier diagnostic approach of using a screening measure followed by confirmation of the screen positive cases with reference standard clinical criterion, improves the sensitivity and specificity. The multiaxial treatment has the advantage of offering a holistic approach to the intervention and improve prognosis from the interacting axes. The primary-care physician should be aware of the medications of choice for the Priority Mental Health Disorders and their drug interactions. Finally, referral of cases with atypical presentations, multiple comorbidities and poor response to the first-line of treatment needs referral to the next tier in the system.     

Utility of pediatric female fertility preservation discussions following pelvic radiation

Introduction

While many childhood cancers are curable with therapy, adverse consequences in fertility exist. We sought to assess the number of female patients with pelvic tumors receiving radiation therapy, and the proportion that undergo measures for fertility preservation (FP).

Methods

A total of 53 female patients treated with pelvic tumors from 2000 to 2016 were retrospectively identified.

Results

19 (34%) of these patients underwent pelvic radiation therapy (pXRT). Three of the patients received pXRT for palliative treatment. Of the 19 female patients receiving pXRT, six (31%) were prepubertal and 13 (68%) were postpubertal. Three patients (16%) had documentation of a discussion of FP measures prior to pXRT. One was prepubertal and the others were post-pubertal. Six patients (32%) were evaluated by endocrinology after radiation therapy, diagnosed with ovarian failure, and placed on hormone therapy. Current guidelines recommend discussion of FP in pre-and postpubertal patients with cancer. This 16-year retrospective review of female patients that underwent pXRT for pelvic tumors demonstrated?<?17% of patients have documentation of a discussion of FP measures.

Conclusion

Female pediatric patients who underwent chemotherapy and pXRT suffer a high rate of premature ovarian failure, high morbidity and mortality as well as low rates of documented FP discussions. Based on these findings we have established a multi-disciplinary fertility preservation team available for consultation and a protocol for discussing and documenting the impact of pXRT, along with other treatments, on fertility.

Level of evidence

III.