Series
Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults

https://doi.org/10.1016/S2213-8587(15)00039-XGet rights and content

Summary

Preservation of gonadal function is an important priority for the long-term health of cancer survivors of both sexes and all ages at treatment. Loss of opportunity for fertility is a prime concern in both male and female cancer survivors, but endocrine effects of gonadal damage are likewise central to long-term health and wellbeing. Some fertility preservation techniques, such as semen and embryo cryopreservation, are established and successful in adults, and development of oocyte vitrification has greatly improved the potential to cryopreserve unfertilised oocytes. Despite being recommended for all pubertal male patients, sperm banking is not universally practised in paediatric oncology centres, and very few adolescent-friendly facilities exist. All approaches to fertility preservation have specific challenges in children and teenagers, including ethical, practical, and scientific issues. For young women, cryopreservation of ovarian cortical tissue with later replacement has resulted in at least 40 livebirths, but is still regarded as experimental in most countries. For prepubertal boys, testicular biopsy cryopreservation is offered in some centres, but how that tissue might be used in the future is unclear, and so far no evidence suggests that fertility can be restored. For both sexes, these approaches involve an invasive procedure and have an uncertain risk of tissue contamination in haematological and other malignancies. Decision making for all these approaches needs assessment of the individual's risk of fertility loss, and is made at a time of emotional distress. Development of this specialty needs better provision of information for patients and their medical teams, and improvements in service provision, to match technical and scientific advances.

Introduction

Treatment for cancer can affect reproductive and endocrine function in both men and women, and loss of fertility is a major concern for patients.1 Although survival rates in young people with cancer were low in the 1960s, major advances in treatment—especially use of multiagent chemotherapy—and in supportive care have resulted in substantially increased numbers of patients being cured during the past 5 decades. Cancer affects one in 800 children: data suggest that around 80% will be alive 5 years from diagnosis and 70% will become long-term survivors. With increasing numbers of long-term survivors, gonadal function and fertility have become important concerns for these young men and women.

If the planned treatment is deemed to put gonadal function and future fertility at risk, fertility preservation options should be considered and discussed with the patient before treatment commences. Although evidence suggests that the greater awareness, knowledge, and willingness needed by oncologists to discuss fertility issues is increasing,2, 3 many patients receive little information.4, 5 Discussion of fertility prognosis at the time of diagnosis is an additional burden for the treatment team, but can have a positive psychological effect on the patient and their family, and can be acceptable even if no realistic fertility preservation options are available.6, 7 New approaches for fertility preservation have been developed, with rapid translation of some into clinical practice. Discussion about whether approaches are experimental (which should therefore be offered only in the context of an approved clinical trial) is especially important when counselling patients who are about to commence cancer treatment. In this Series paper, we discuss assessment of risk to fertility and possible mechanisms of gonadal damage, and propose a schema-based approach to counselling for individual patients.

Section snippets

Which patients are at risk?

Consideration of the extent of risk to gonadal function in both male and female patients is crucial for provision of the most accurate information to patients, and enables investigation of potential fertility preservation strategies, which can be time consuming, invasive, and in some cases experimental.8 Risk of infertility for some young men and women is low, whereas other patients will almost certainly lose gonadal function. Consideration of this risk can be usefully structured into intrinsic

How is fertility lost?

The infertility experienced by some patients after cancer treatment is most often due to a loss of germ cells, but whether that loss is a direct result of treatment or an indirect effect is less clear, with such information important for the design of protective treatment. Mechanistic examination of damage is complex because the mechanisms of action vary across different chemotherapy drug classes and between chemotherapy and radiotherapy treatment, and because most patients receive combination

Endocrine effects of gonadal damage from cancer therapy

Although loss of fertility is a major concern for both male and female cancer survivors, the non-fertility or endocrine effects of gonadal damage are important for long-term health. In female patients, the close association between germ cells and endocrine cells of the ovary in the growing follicle means that when one is lost or damaged, then both are. So, in the worst case, in which all follicles are lost, the patient has premature ovarian insufficiency, and thus oestrogen deficiency and

What can be done?

Fertility preservation is part of the UK National Institute for Health and Care Excellence guidance for management of people diagnosed with cancer,83 and some options are well established. These options include semen cryopreservation for adult men, and embryo and oocyte cryopreservation for women. For both sexes, options for children and adolescents are experimental. We discuss direct measures for fertility preservation (gamete and gonadal tissue cryopreservation) (figure 5); we briefly discuss

Protection of the gonad in situ

In patients who are about to undergo radiotherapy in the abdominopelvic region, shielding of the gonad from the radiotherapy beam might be possible. In young men, shielding of the gonad has been shown to preserve testicular growth and function when used in combination with bone marrow transplantation.84 However, special care needs to be taken in girls to correctly identify the position of the ovaries.85 Improvements in radiotherapy techniques might also result in specific targeting to the

For male patients

For prepubertal boys, strategies for fertility preservation are experimental and can be broadly classified into strategies in which the gonad is protected in situ and those in which gonadal tissue is removed for cryostorage and future use in reproductive technologies. Approaches for protection of the gonad in situ include changing the hormonal milieu to render the gonad insensitive to the effects of cancer treatment. Although studies in rodents with gonadotropin-releasing hormone analogues, sex

Conclusions and future directions

Substantial progress has been made in the techniques and provision of fertility preservation for young people with cancer in the past 20 years. Semen and embryo cryopreservation, and oocyte vitrification, are established procedures in appropriate cases, with oocyte vitrification greatly improving options for young women. Although experimental, ovarian tissue cryopreservation is widely used in women and in some children and adolescents. This technique is likely to become more widely offered to

Search strategy and selection criteria

We searched Medline between Jan 1, 1990, and Sept 1, 2014, for reports published in English using the search terms “fertility preservation”, “cancer”, “childhood cancer”, “gonadotoxic”, and “cancer treatment” in several disjunctive and conjunctive combinations. We mainly selected publications in English from the past 5 years, but did not exclude older, important publications. Additionally, we checked the reference lists of articles identified by this search strategy.

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