W. Hamish B. Wallace

Fertility preservation for young patients with cancer: who is at risk and what can be offered?

Estimates suggest that by 2010, one in 715 people in the UK will have survived cancer during childhood. With increasing numbers of children cured, attention has focused on their quality of life. We discuss the causes of impaired fertility after cancer treatment in young people, and outline which patients are at risk and how their gonadal function should be assessed. With the report of a livebirth after orthotopic transplantation of cryopreserved ovarian tissue and the continued development of intracytoplasmic sperm injection for men with poor sperm quality, we assess established and experimental strategies to protect or restore fertility, and discuss the ethical and legal issues that arise.

Human ovarian reserve from conception to the menopause.

The human ovary contains a fixed number of non-growing follicles (NGFs) established before birth that decline with increasing age culminating in the menopause at 50–51 years. The objective of this study is to model the age-related population of NGFs in the human ovary from conception to menopause. Data were taken from eight separate quantitative histological studies (n = 325) in which NGF populations at known ages from seven weeks post conception to 51 years (median 32 years) were calculated. The data set was fitted to 20 peak function models, with the results ranked by obtained correlation coefficient. The highest ranked model was chosen. Our model matches the log-adjusted NGF population from conception to menopause to a five-parameter asymmetric double Gaussian cumulative (ADC) curve ( = 0.81). When restricted to ages up to 25 years, the ADC curve has  = 0.95. We estimate that for 95% of women by the age of 30 years only 12% of their maximum pre-birth NGF population is present and by the age of 40 years only 3% remains. Furthermore, we found that the rate of NGF recruitment towards maturation for most women increases from birth until approximately age 14 years then decreases towards the menopause. To our knowledge, this is the first model of ovarian reserve from conception to menopause. This model allows us to estimate the number of NGFs present in the ovary at any given age, suggests that 81% of the variance in NGF populations is due to age alone, and shows for the first time, to our knowledge, that the rate of NGF recruitment increases from birth to age 14 years then declines with age until menopause. An increased understanding of the dynamics of human ovarian reserve will provide a more scientific basis for fertility counselling for both healthy women and those who have survived gonadotoxic cancer treatments.

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.

Toxicity of Chemotherapy and Radiation on Female Reproduction

One of the most devastating consequences of cancer treatment in the young female population is ovarian damage, resulting in diminished fertility potential. The extent of damage is related to age, chemotherapeutic regimen, and dose of pelvic radiation received. It is crucial that physicians know the impact each of these factors has on future fertility to advice patients on fertility preservation options. Anticancer drugs injure the female reproductive system through ovarian follicular and stromal damage. Although the exact mechanisms of damage remain unclear, it is essential to better understand these mechanisms to develop methods to diminish ovarian injury.

Developing strategies for long term follow up of survivors of childhood cancer

The treatment of childhood cancer has been increasingly successful over the past 30 years. Most paediatric cancers are now curable with multiagent chemotherapy in combination with surgery and radiotherapy. The overall survival five years after diagnosis is now 70% for all paediatric malignancies. The incidence is low (1200-1300 children affected each year in Britain), but with the sustained improvement in survival the number of long term survivors is increasing—about 850 additional survivors of childhood cancer each year. With this improved survival, it is important to increase our knowledge of any long term costs in the form of physical and psychosocial adverse health outcomes. This review looks at the evidence relating to long term clinical follow up after childhood cancer and considers ways to develop such follow up for the future. An awareness of the possible long term complications is important not only for optimising health care for the current survivors but also for modifying future treatment protocols to avoid therapies that are associated with unacceptable morbidity or mortality. We have summarised the evidence on selected long term complications; this evidence is inevitably based on retrospective studies. In the final section we discuss the development of a strategy for the clinical follow up of long term survivors. #### Summary points Long term follow up strategies are needed because of increasing numbers of survivors of childhood cancers Models for follow up need to be developed and formally evaluated Increasing numbers of survivors may have medical problems that will require ongoing specialist follow up The role, training programmes, and career structure of the late effects nurse practitioner needs to be developed The primary care physician may have an important role in long term follow up There is a need for prospective evaluation of new treatments and randomised studies of clinical interventions to resolve substantial uncertainties for …

Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement

Objective To study the effect of total body irradiation (14.4 Gray) in childhood and adolescence on ovarian and uterine characteristics, and to investigate the response to physiological sex steroid serum concentrations.

Semen quality and spermatozoal DNA integrity in survivors of childhood cancer: a case-control study.

BACKGROUND Treatment of childhood cancer can result in impaired spermatogenesis. Intracytoplasmic sperm injection (ICSI), however, can enable men to achieve fatherhood, and has focused attention on gamete integrity in men with oligozoospermia. Our aim was to assess testicular function in survivors of childhood cancer. METHODS We assessed testicular function in 33 survivors of childhood cancer and 66 age-matched controls. The median age at diagnosis and at the start of the trial was 10.0 years (range 2.2-16.9) and 21.9 years (16.5-35.2), respectively. We assessed pubertal staging, measured plasma sex steroid hormone concentrations, and analysed semen quality, including spermatozoal DNA integrity. FINDINGS Ten (30%) individuals were azoospermic and six (18%) oligozoospermic (sperm concentration, 20 x 10(6)/mL). Sperm concentration was significantly lower in the non-azoospermic group than in controls (median 37.1 x 10(6)/mL, IQR 19.7 x 10(6) to 89.9 x 10(6), vs 90.7 x 10(6)/mL, 50.5 x 10(6) to 121.5 x 10(6); p=0.002). In the non-azoospermic cancer survivor group, inhibin B concentrations were lower than in controls (mean 153.3 ng/L, SEM 17.8, vs 223.7 ng/L, 8.8; p,0.001), and FSH concentrations were higher (6.6 U/L, 0.9, vs 3.2 U/L, 0.2; p,0.001). Only 11 (33%) survivors of childhood cancer had normal semen quality. There was no significant difference in sperm DNA integrity between the non-azoospermic and control groups (9%, 5-13, vs 11%, 7-16; p=0.06). INTERPRETATION Sperm concentration is reduced after treatment for cancer. However, the sperm produced seems to carry as much healthy DNA as those produced by the healthy population, suggesting that assisted conception can be considered as a treatment option for these men.

Recommendations for Cardiomyopathy Surveillance for Survivors of Childhood Cancer: A Report from the International Late Effects of Childhood Cancer Guideline Harmonization Group

Survivors of childhood cancer treated with anthracycline chemotherapy or chest radiation are at an increased risk of developing congestive heart failure. In this population, congestive heart failure is well recognised as a progressive disorder, with a variable period of asymptomatic cardiomyopathy that precedes signs and symptoms. As a result, several clinical practice guidelines have been developed independently to help with detection and treatment of asymptomatic cardiomyopathy. These guidelines differ with regards to definitions of at-risk populations, surveillance modality and frequency, and recommendations for interventions. Differences between these guidelines could hinder the effective implementation of these recommendations. We report on the results of an international collaboration to harmonise existing cardiomyopathy surveillance recommendations using an evidence-based approach that relied on standardised definitions for outcomes of interest and transparent presentation of the quality of the evidence. The resultant recommendations were graded according to the quality of the evidence and the potential benefit gained from early detection and intervention.

Anti-Müllerian Hormone Is a Marker of Gonadotoxicity in Pre- and Postpubertal Girls Treated for Cancer: A Prospective Study

CONTEXT Cytotoxic treatment may accelerate depletion of the primordial follicle pool, leading to impaired fertility and premature menopause. Assessment of ovarian damage in prepubertal girls is not currently possible, but Anti-Müllerian Hormone (AMH) is a useful marker of ovarian reserve in adults. OBJECTIVE The objective of the study was to prospectively evaluate AMH measurement in children as a marker of ovarian toxicity during cancer treatment. DESIGN AND SETTING This was a prospective, longitudinal study at a University Hospital. PATIENTS Twenty-two females (17 prepubertal), median age 4.4 yr (range 0.3-15 yr), were recruited before treatment for cancer. MAIN OUTCOME MEASURES AMH, inhibin B, and FSH at diagnosis, after each chemotherapy course and during follow-up, were measured. Risk of gonadotoxicity was classified as low/medium (n = 13) or high (n = 9) based on chemotherapy agent, cumulative dose, and radiotherapy involving the ovaries. RESULTS Pretreatment AMH was detectable across the age range studied. AMH decreased progressively during chemotherapy (P < 0.0001) in both prepubertal and pubertal girls, becoming undetectable in 50% of patients, with recovery in the low/medium risk groups after completion of treatment. In the high-risk group, AMH became undetectable in all patients and showed no recovery. Inhibin B was undetectable in most patients before treatment and, with FSH, showed no clear relationship to treatment. CONCLUSION AMH is detectable in girls of all ages and falls rapidly during cancer treatment in both prepubertal and pubertal girls. Both the fall during treatment and recovery thereafter varied with risk of gonadotoxicity. AMH is therefore a clinically useful marker of damage to the ovarian reserve in girls receiving treatment for cancer.

A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group

Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010, the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence‐based methods, we provide a framework for the harmonization of guidelines for the long‐term follow‐up of childhood and young adult cancer survivors. Pediatr Blood Cancer 2013; 60: 543–549.