Oncofertility and preservation of reproductive capacity in children and young adults§

Authors

  • W. Hamish B. Wallace MD, FRCP

    Corresponding author
    1. Department of Pediatric Haematology/Oncology, Royal Hospital for Sick Children, Edinburgh, Scotland, United Kingdom
    • Royal Hospital for Sick Children, Edinburgh EH9 1LF, Scotland, UK
    Search for more papers by this author
    • Fax: (011) 00441315360430


  • Some of the ideas and thoughts presented in this review have been published in review articles authored or coauthored by the author.

  • The articles in this supplement represent presentations and discussions at the “International Workshop on Adolescents and Young Adults with Cancer: Towards Better Outcomes in Canada” that was held in Toronto, Ontario, March 11-13, 2010.

  • §

    *Workshop on Adolescents and Young Adults with Cancer: Towards Better Outcomes in Canada, Supplement to Cancer.

Abstract

With increasing numbers of survivors from cancer at a young age, the issue of fertility preservation has assumed greater importance. This review describes normal ovarian and testicular function and summarizes what is known about the effect of chemotherapy and radiotherapy on the gonads and uterus. All young patients with cancer or leukemia should have their fertility prognosis discussed before the initiation of treatment. Sperm and embryo cryopreservation should be considered standard practice and be widely available for those at significant risk of infertility. For prepubertal girls, ovarian tissue cryopreservation should be considered if the risk of premature menopause is high, but for the prepubertal boy there are no established techniques in current practice. Cancer 2011;117(10 suppl):2301–10. © 2011 American Cancer Society.

Cancer in childhood and adolescence is rare, with approximately 1400 new cases per year diagnosed in patients aged < 16 years in the UK, and a cumulative risk of approximately 1 in 500 by the age of 15 years. Information for teenagers and young adults is less easy to find, but in 2005 there were 2250 cases of cancer diagnosed in individuals ages 15 to 24 years in the United Kingdom (Cancer Incidence and Mortality By Cancer Network, UK, 2005. Available at: www.ncin.org.uk). With long-term survival rates in excess of 70%, it is anticipated that, by the year 2010, approximately 1 in 640 to 715 members of the adult population will be a long-term survivor of childhood cancer.1-3

Impaired fertility in both males and females and adverse pregnancy outcomes are major concerns for the increasing population of survivors of childhood and young adult cancer. The challenge facing professionals is how to provide curative treatment while balancing the potential loss or impairment of fertility. Chemotherapy regimens differ widely in their effect on fertility. Highly gonadotoxic regimens include alkylating agents such as procarbazine. Radiotherapy also carries a high risk when there is a direct or scatter dose to the gonad. There are an increasing number of retrospective studies but very few prospective studies assessing gonadal function and fertility in survivors of childhood cancer in relation to treatment received. One of the difficulties is that treatment regimens are constantly evolving, and there is a need for many years of follow-up for children treated prepubertally to determine accurately the fertility outcome.

In addition to uncertainty over the risk of infertility associated with different treatment regimens, techniques available for fertility preservation in children and young adults are limited and their risk-to-benefit ratio unclear. With improved survival, there is a responsibility to improve our understanding of the risks to the gonads associated with successful treatment and address what can be done to preserve fertility, before treatment starts, in the minority of patients who are at high risk of infertility or premature menopause.

Normal Ovarian Function

It is widely believed that the human ovary establishes several million nongrowing follicles (NGF) at around 5 months of gestational age, which is followed by a rapid decline until menopause, when approximately 1000 remain at an average age of 50 to 51 years.4 With approximately 450 ovulatory monthly cycles in the normal human reproductive lifespan from menarche until menopause, this progressive decline in NGF numbers is attributed to follicle death by apoptosis. Premature menopause is usually considered to be the cessation of menses before the age of 40 years. Acute ovarian failure is used by some researchers to describe the complete cessation of ovarian function shortly after cancer treatment.

There have been several recent reports that have challenged this long-held understanding of mammalian reproductive biology by reporting the presence of mitotically active germ stem cells in juvenile and adult mouse ovaries.5, 6 There is no doubt that the presence of germ stem cells within the mammalian ovary that are capable of neo-oogenesis is controversial.7 If we can acquire a better understanding of the establishment and decline of the NGF population from conception to menopause, this will be helpful in determining if neo-oogenesis occurs as part of normal human physiological ageing. In this regard, we have recently identified what to our knowledge is the first model of human ovarian reserve from conception to menopause that best fits the combined histological evidence.8 This model allows us to estimate the number of NGF present in the ovary at any given age (Fig. 1). It is interesting to note that this model suggests that 81% of the variance in NGF populations is due to age alone. The remaining 19% is because of factors other than age (eg, smoking, body mass index, parity, and stress). We can speculate that, as chronological age increases, factors other than age become more important in determining the rate at which NGF are lost through apoptosis. By further analysis of this model, we have also shown that the rate of NGF recruitment toward maturation increases from birth to age 14 years and then declines with age until menopause. The mechanisms responsible for controlling NGF recruitment toward maturation in the human ovary remain unclear, but it is unlikely to be coincidental that the maximum age at recruitment is around the onset of menarche and the establishment of regular menstrual cycles.

Figure 1.

Illustrative examples of nongrowing follicles (NGF) populations predicted by our model are shown. The average NGF population at ages 20 weeks after conception, birth, 13 years, 25 years, and 35 years is given, together with the respective 95% prediction intervals (95% PI). The predicted average age at menopause (49.6 years) is also shown, together with the 95% PI. Abbreviations: Max, maximum. Reprinted with permission from Wallace WH, Kelsey TM. Human ovarian reserve from conception to menopause. PloS One. 2010;5:e8772.

Radiation and the Hypothalamic-Pituitary-Ovarian Axis

The ovaries may be damaged and the number of NGF present reduced after total body irradiation (TBI), abdominal irradiation, or pelvic irradiation and the extent of the damage is related to the radiation dose, fractionation schedule, and patient age at the time of treatment.9 Earlier studies have shown that the human oocyte is sensitive to radiation, with an estimated median lethal dose (LD50) of < 2 gray (Gy).10 The number of primordial follicles present at the time of treatment, together with the dose received by the ovaries, will determine the fertility “window” and influence the age of premature ovarian failure. Ovarian failure has been reported in 90% of patients followed long term after TBI (10-15.75 Gy) and in 97% of females treated with total abdominal irradiation (20-30 Gy) during childhood.11, 12 Using our knowledge and understanding of the radiosensitivity of human oocytes, it is now possible to predict the estimated sterilizing dose after any given dose of radiotherapy at any given age based on the application of the mathematical solution to our model for natural oocyte decline (Fig. 2).13 This will help clinicians to provide more accurate information when counseling women about their fertility prospects after treatment of childhood cancer. Those women at an estimated high risk for premature menopause should be considered for fertility preservation technologies.

Figure 2.

Based on our understanding of the radiosensitivity of the human oocyte and our knowledge of the natural decline in primordial follicles with increasing age, we provide effective (red line) and mean (blue line) estimates of the dose required to sterilize a patient at a known age of treatment. Abbreviations: Gy, gray. Reprinted with permission from Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys. 2005;62:738-744

Gonadotropin deficiency after high-dose cranial irradiation (> 24 Gy in the treatment of brain tumors) may be manifest as delayed puberty or absent menses and can be treated with hormone replacement therapy. It is interesting to note that early puberty is often reported, particularly in females treated with cranial radiation doses of < 24 Gy.14 However, it has been shown that after low-dose cranial radiotherapy (18-24 Gy), there is a subtle decline in hypothalamic-pituitary-ovarian function as characterized by decreased luteinizing hormone (LH) secretion, an attenuated LH surge, and shorter luteal phases that are likely to herald incipient ovarian failure or be associated with early pregnancy loss.15

Cancer Treatment and Ovarian Function

The ovary is also susceptible to chemotherapy-induced damage, particularly after treatment with alkylating agents such as cyclophosphamide, often as part of the treatment of Hodgkin lymphoma (HL).16, 17 Ovarian damage is drug and dose dependent and is related to the patient's age at time of treatment, with progressively smaller doses required to produce ovarian failure with increasing age.18 It is important to emphasize that there is no evidence that the prepubertal ovary is protected from chemotherapy or radiotherapy. Cyclophosphamide is widely used in combination chemotherapy regimens, in which its effect on ovarian function is related to both the dose used and the age of the patient. High-dose cyclophosphamide (200 mg/kg) is frequently used as conditioning therapy before bone marrow transplantation (BMT), either alone, when recovery of ovarian function is more likely, or in combination with other chemotherapeutic agents or TBI.11

In the past, the treatment of HL with the combination of mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP) or chlorambucil, vinblastine, procarbazine, and prednisolone (ChLVPP) has been reported to be associated with ovarian dysfunction in 19% to 63% of cases.19 Acute ovarian failure and premature menopause are more commonly encountered in older women. In younger women, although long-term follow-up is necessary, it is likely that an increasing number will develop premature menopause. In a recent cohort study of 518 female 5-year survivors of HL ages 14 to 40 years (median, 25 years) at the time of treatment, the Amsterdam group explored the incidence of premature menopause before the age of 40 years. Alkylating agents, especially procarbazine (hazard ratio [HR], 8.1) and cyclophosphamide (HR, 3.5), demonstrated the strongest associations. Ten years after treatment, the actuarial risk of premature menopause was 64% after high cumulative doses (> 8.4 g/m2) and 15% after low cumulative doses (≤ 4.2 g/m2) of procarbazine.20 This study also confirmed that women who were older at the time of first treatment experienced premature menopause sooner after treatment than younger women. Current treatment in Europe (EuroNet) of patients aged < 18 years with HL seeks to randomize procarbazine versus dacarbazine in patients with intermediate and advanced stage disease with the objective of demonstrating that dacarbazine is less likely to cause premature ovarian failure (and damage to the germinal epithelium of the testis in males) than procarbazine-containing regimens, but is as efficacious.

Chemotherapy with doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) remains a common and successful first-line treatment protocol for young people with HL. In a study of 26 ovarian tissue samples harvested for cryopreservation from women with HL, there was no evidence of HL involvement in any of the samples examined. Seven of 20 patients had received ABVD chemotherapy before the tissue harvest and demonstrated no difference in follicle density compared with patients who underwent tissue harvest before treatment (n = 14) (median, 1555 mm3 vs 1620 mm3; P = .97). Importantly, this study did not identify subclinical involvement of HL in ovarian tissue, even when patients had infradiaphragmatic disease.21

The Childhood Cancer Survivor Study (CCSS) was established as a resource for investigating the long-term outcomes of a cohort of 5-year survivors of childhood and adolescent cancer who were diagnosed between 1970 and 1986. With a cohort of > 14,000 active participants, it is to our knowledge the largest epidemiological study investigating long-term outcomes and quality of life in survivors who currently are ≥ 20 years past their initial treatment. These studies have demonstrated that women treated with pelvic irradiation and/or increasing doses of alkylating agents are at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence of an increased risk of congenital malformations.22 As this cohort of 5-year survivors of childhood cancer ages, the prevalence of ovarian failure is likely to increase.

The assessment of ovarian reserve in the young woman who has been successfully treated for cancer remains difficult. Larsen et al evaluated ovarian function in 100 childhood cancer survivors and 21 controls of similar age.23 Survivors with spontaneous menstrual cycles (n = 70) were found to have smaller ovarian volume per ovary compared with controls (median, 4.8 cm3 vs 6.8 cm3; P < .001) and a lower number of antral follicles (AFC) per ovary (median, 7.5 AFC vs 11 AFC; P < .001). A regression analysis was performed to predict the total AFC number per ovary, which demonstrated a reduced number in women who were treated with ovarian irradiation (β = −.40; P < .001), alkylating chemotherapy (β = −.25; P = .01), older age at diagnosis (β = −.25; P = .01), and longer time period off treatment (β = −.19; P = .044).23 A recent study in women aged <40 years24 has suggested that, compared with inhibin B and AFC, anti-Mullerian hormone (AMH) was more consistently correlated with the clinical degree of follicle pool depletion in young women presenting with elevated follicle-stimulating hormone (FSH) levels. Further evidence that AMH will be useful in the assessment of the young woman who has been treated for cancer comes from a study of women treated during childhood for HL.25 Those women who received MOPP chemotherapy were shown to have a reduced ovarian reserve as measured by lower AMH values at early adulthood, compared with healthy women. In this study, AMH was found to be the only predictor that was sufficiently sensitive to detect this decrease in ovarian reserve. More research is required to determine the role of the measurement of AMH in predicting age at menopause and ovarian reserve in young women who have been successfully treated for cancer.

Radiation and the Uterus

After abdominal, pelvic, or TBI, the uterus is at risk of damage in a dose- and age-dependent manner.26 Uterine function may be impaired after radiation doses of 14 to 30 Gy as a consequence of disruption to the uterine vasculature and musculature elasticity.27 Even lower dose of irradiation, as in TBI, have been reported to cause impaired growth and blood flow.27

Efforts to improve uterine function have been tried, with limited success. In young adult women previously treated with TBI, physiological sex steroid replacement therapy was found to improve uterine function (blood flow and endometrial thickness) and may potentially enable these women to benefit from assisted reproductive technologies.27 Larsen et al studied uterine volume in 100 childhood cancer survivors and assessed uterine response to high-dose estrogen replacement in 3 patients with ovarian failure and reduced uterine volume after abdominal and/or pelvic irradiation.28 There was no significant difference noted with regard to uterine volume, endometrial thickness, or uterine artery blood flow after sex steroid therapy. The results of this study suggest that damage to the uterus is dose dependent, with higher doses (often as part of direct radiation to the pelvis) causing more damage compared with lower doses (as in TBI), and this damage may be irreversible.

Radiotherapy causes both ovarian and uterine damage. To my knowledge, there are no reports of uterine damage after chemotherapy. Uterine damage as manifested by impaired growth and blood flow is a likely consequence of radiation to a field that includes the pelvis. Exposure of the pelvis to radiation is associated with an increased risk of miscarriage, mid-trimester pregnancy loss, preterm birth, and low birth weight. The optimal dose and delivery route of estrogen replacement required to facilitate uterine growth in adolescent women treated with TBI needs to be established.

Normal Testicular Function

The major functions of the male reproductive tract are 2-fold: to manufacture and deliver spermatozoa to the female reproductive tract and to produce male sex steroid hormones, necessary for sexual development during fetal life, puberty, male phenotype and behavior, and reproduction. The anterior pituitary hormones FSH and LH, under the controlling influence of hypothalamic gonadotropin-releasing hormone (GnRH), regulate testicular function. In turn, the hypothalamic-pituitary-testicular axis is influenced by the secretion of testicular hormones, including inhibin and testosterone.

The testes are comprised of 2 structurally distinct but functionally related compartments, the seminiferous tubules and intertubular space, sites of spermatogenesis and steroidogenesis, respectively. The tubules are lined with seminiferous epithelium comprised of various types of male germ cells (spermatogenic cells) and a single type of supporting cell, the Sertoli cell. Testosterone, essential for spermatogenesis, is synthesized and secreted by the Leydig cells in response to stimulation by LH, and passes through the cellular barriers to the Sertoli cell, with a substantial amount entering the blood and lymphatic system. Testosterone functions primarily as a prohormone, converted to the potent androgen dihydrotestosterone (DHT) via the enzyme 5-α reductase and to the estrogen 17-β estradiol through the aromatase enzyme. FSH and testosterone act synergistically on Sertoli cells to promote Sertoli cell function and support spermatogenesis because germ cells per se do not possess receptors for either hormone. The mechanism by which spermatogenesis is initiated and sustained is poorly understood and is likely to involve several stimulatory and inhibitory pathways. Testosterone exerts a negative feedback regulation of the hypothalamic and pituitary hormones.

Spermatogenesis is a complex process by which diploid germ cell spermatogonia undergo proliferation and differentiation into mature haploid spermatozoa. The general organization of spermatogenesis is essentially the same in all mammals and can be divided into phases of development through which all spermatogenic germ cells pass sequentially over time. The time taken from the division of 1 stem cell spermatogonium to the production of mature spermatozoa varies between species, and in humans is determined to be 74 days.

The Effect of Radiotherapy on Testicular Function

In males, radiation doses as low as 0.1 to 1.2 Gy can impair spermatogenesis, with doses > 4 Gy causing permanent azoospermia. The somatic cells of the testis are more resistant than the germ cells, and Leydig cell dysfunction is not observed until doses of 20 Gy in prepubertal boys and 30 Gy in sexually mature males.29

Within the pediatric and adolescent age groups, testicular damage occurs with direct irradiation of the testes (eg, in the management of leukemia).30 In patients with leukemic infiltration of their testes, radiation doses of 24 Gy are used, and this results in permanent azoospermia.31 TBI as conditioning treatment before BMT will also irradiate the testes, and although the effects of this can be difficult to elucidate because it is usually administered concurrently with alkylating agents, doses of 9 to 10 Gy have produced gonadal dysfunction.32

A recent study from the CCSS was reassuring with regard to heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men who were fertile but had been exposed to gonadal irradiation.33

The Effect of Chemotherapy on the Testis

As with radiotherapy, the germinal epithelium of the testis is very sensitive to the detrimental effects of chemotherapy irrespective of the patient's pubertal status at the time of treatment. Therefore, after receiving gonadotoxic agents, patients may be rendered oligospermic or azoospermic but testosterone production by the Leydig cell is usually unaffected, and thus secondary sexual characteristics develop normally.34 After higher cumulative doses of gonadotoxic chemotherapy, Leydig cell dysfunction may also become apparent.35

The treatment of HL has involved the use of procarbazine together with alkylating agents such as chlorambucil, mustine, and cyclophosphamide. Although these drug combinations have resulted in excellent survival rates, the majority of male patients have subsequently developed permanent azoospermia.36, 37 Mackie et al19 studied patients with a mean age at diagnosis of 12.2 years who were treated with ChLVPP, a regimen containing both chlorambucil and procarbazine. On follow-up, 89% of these patients demonstrated severe damage to the seminiferous epithelium up to 10 years after therapy. Because of this, treatment for HL has been modified in an attempt to reduce gonadotoxicity while maintaining long-term survival.19 Treatment with the ABVD regimen, which contains no alkylating agents or procarbazine, results in significantly less gonadotoxicity, with no patients demonstrating permanent azoospermia.36 However, anthracycline exposure in this regimen renders it potentially cardiotoxic in the long term.38

Pregnancy in High-Risk Survivors of Cancer

Survivors of childhood cancer who have received radiotherapy to a field that includes their pelvis should be considered to be at high risk for uterine dysfunction in pregnancy. There is good evidence that these pregnancies may be associated with an increased risk of adverse outcomes such as prematurity and miscarriage.

Adverse pregnancy-related outcomes in survivors of childhood cancer have been explored in a few small studies. We studied pregnancy outcomes in female survivors of Wilms tumor who received irradiation to the flank, abdomen, or pelvis and reported an increased risk of premature birth and/ or low birth weight.12 As previously discussed, the CCSS cohort of adult survivors reported great concern regarding their fertility and the health of their offspring. The CCSS examined pregnancy outcomes in both male and female survivors in comparison with their sibling cohort.39, 40 The offspring of female survivors were more likely to be born before 37 weeks of gestation compared with those of their female siblings (21.1% vs 12.6%; odds ratio [OR], 1.9 [95% confidence interval (95% CI), 1.4 to 2.4]; P < .001). Preterm birth was more likely for the offspring of those women who received uterine radiation doses ≥ 0.05 Gy compared with those who received no radiotherapy (0.05-2.50 Gy [26.1% vs 19.6%]: OR, 1.8 [95% CI, 1.1 to 3.0], P = .03; 2.5 to 5.0 Gy [39.6% vs 19.6%]: OR, 2.3 [95% CI, 1.0-5.1], P = .04; and > 5 Gy [50.0% vs 19.6%]: OR, 3.5 [95% CI, 1.5-8.0], P = .003). The offspring of women who received uterine radiation doses > 5 Gy were more likely to be small for gestational age (birth weight below the 10th percentile for gestational age [18.2% vs 7.8%]: OR, 4.0 [95% CI, 1.6-9.8], P = .003). The frequency of premature birth was not found to be increased by previous maternal exposure to increasing doses of chemotherapy with alkylating agents. These important large studies have shown that the offspring of women whose treatment included pelvic irradiation are more likely to be premature, have a low birth weight, and be small for their gestational age. The results of these studies have also demonstrated that the risk of miscarriage was increased among women whose treatment included high-dose cranial or craniospinal irradiation.

In conclusion, these large studies did not identify adverse pregnancy outcomes for female survivors treated with most chemotherapeutic agents; however, the offspring of women who received pelvic irradiation were reported to be at risk for low birth weight.39, 40

Options for Fertility Preservation in Female Patients

Female fertility preservation provides significantly different challenges from that for the male patient. To my knowledge, there are currently only 2 established practices of fertility preservation in female patients. The first is oophoropexy and the second is cryopreservation of embryos after in vitro fertilization. Oophoropexy (surgically displacing the ovaries out of the radiation field) may preserve ovarian function but radiation-induced uterine damage may still affect the chances of successful pregnancy. Cryopreservation of embryos is only suitable for sexually mature women with a partner but is not available for children or young adults who do not have a partner. Mature oocyte preservation is a potential solution for women without a partner but pregnancy rates are significantly lower because these cells sustain more damage during the freeze-thawing process in comparison with embryos. Significant delays in cancer treatment may occur because these techniques require ovarian stimulation with oocyte retrieval. However, for the young patient, cryopreservation of ovarian cortical tissue collected laparoscopically is extremely promising, with approximately 30 cases of autotransplanted, frozen-thawed ovarian tissue reported to have lead to the births of 10 live infants to date.41 Ovarian tissue cryopreservation has the potential advantages of preserving a large number of oocytes within primordial follicles, it does not require hormonal stimulation when time is short, and it is appropriate for the prepubertal girl. Disadvantages include the need for an invasive procedure and the uncertain risk of ovarian contamination in hematological and other malignancies.

We have published our own experience of ovarian cryopreservation in 36 women considered to be at high risk of experiencing premature menopause. Of these 36 women, 11 had died at the time of last follow-up, but 5 experienced spontaneous pregnancies, with none to date having requested reimplantation of their stored ovarian tissue.42 The most common diagnoses have been hematological malignancies (lymphoma and leukemia; n = 11). Sarcoma (n = 10) was the most common solid malignancy. Approximately 20% of the women had inflammatory rather than malignant diagnoses, generally systemic lupus erythematosis, and were to be treated with cyclophosphamide-based regimens. The median age at cryopreservation was 19.2 years (range, 5-35 years). Fifteen patients (42%) were aged < 16 years at the time of surgery. As of December 2007, the median age of those surviving was 24.4 years (range, 8.5-43.6 years) and the median duration since cryopreservation was 7.1 years. Of the 20 surviving women currently aged > 18 years, 7 (35%) had experienced spontaneous pregnancies. Five of these pregnancies resulted in term live births, with 1 induced and 1 spontaneous abortion. Of the remaining patients, none was menopausal as of that date. The first patient treated, who underwent high-dose chemotherapy and BMT at age 19 years, retained a regular menstrual cycle with an early follicular phase FSH concentration of < 10 IU/L 13 years later. A total of 11 (31%) of the patients had died at the time of last follow-up. Their diagnoses spanned the range of entities, including those with inflammatory conditions. The majority died within 1 year of diagnosis, and all had died within 5 years. Our experience highlights the difficulty of assessing which patients are at high risk of experiencing premature menopause before treatment has begun. Ovarian cryopreservation appears to be a potentially valuable method for fertility preservation, but the indications and approaches best used remain unclear.43, 44 A fascinating new study has recently been published that describes restoration of ovarian function in 3 women after ovarian allografting between genetically nonidentical sisters in whom a previous BMT from the human leukocyte antigen-compatible sister had resulted in full chimerism and thus the threat of rejection and the requirement for immunosuppressive therapy were avoided.45 With fertility preservation choices for girls and young women including both established and experimental techniques, specialist referral and assessment is important if time permits before treatment commences.46

Preventing chemotherapy-induced damage to the ovary remains an elusive challenge. Most attention has focused on the potential for protecting the ovaries using the gonadotropin-suppressing GnRH analogues. Although a plausible biological explanation for this approach is unclear, because only later stages of follicular growth are gonadotropin-dependent, there is a need for a large, well-designed randomized study to address this controversial issue.

Options for Fertility Preservation in Male Patients

Semen cryopreservation is an established and successful technique for the adult male, but is more challenging to perform in children and teenagers. Sperm banking is not universally practiced in pediatric oncology centers, and to our knowledge there are very few “adolescent-friendly” facilities. After the diagnosis of a malignancy, treatment is usually initiated as soon as possible. After the devastating news of the diagnosis, it can be very difficult for teenagers to then discuss fertility and subsequently produce a semen specimen. Discussions must be dealt with sensitively, and using appropriate language that the patient understands. However, many patients and their families derive benefit from open discussions regarding fertility, particularly as this places an emphasis on the future and provides reassurance that curative treatment is the aim.47

Semen specimens will usually be produced by masturbation in boys who are sufficiently mature and, if not possible, penile vibratory stimulation or rectal electrostimulation under anesthesia can then be considered.48 Alternatively, if spermatogenesis is established, sperm may be retrieved after testicular or epididymal aspiration. In the United Kingdom, the storage of sperm is governed by the Human Fertilization and Embryology Act. One of the implications of this Act is that any individual storing sperm must be capable of understanding the implications of what is proposed, and provide valid written informed consent to storage.

Semen specimens produced by teenagers are frequently of poor quality.49 The freeze-thawing process used for cryopreservation can then cause further damage, resulting in impaired sperm motility and damage to chromatin structure and sperm morphology.

After cryopreservation, stored spermatozoa may be used for in vitro fertilization. With advances in assisted reproduction techniques, particularly intracytoplasmic sperm injection, which involves the injection of a single spermatozoon directly into an oocyte, the problems of low sperm numbers and poor motility may be circumvented.

All male patients who are able to produce semen should have the opportunity of sperm banking before the initiation of treatment. If production of semen by masturbation is not possible, alternative methods of sperm retrieval should be considered if the likelihood of infertility is significant and the patient is sufficiently mature, both physically, with testicular volumes > 10 mL, and emotionally, with a demonstrable understanding of what is involved and why cryopreservation is being offered.50

For patients who have not yet entered puberty, the options for fertility preservation currently remain entirely experimental. Spermatogonial stem cells provide novel strategies for the preservation of testicular tissue and fertility preservation in prepubertal boys for whom there are currently no realistic options. Schlatt et al reviewed the physiology of spermatogonial stem cells in rodent and primate testes and indicated some of the possible future options that require further basic research.51

Conclusions

The American Society of Clinical Oncology concluded that sperm and embryo cryopreservation should be considered standard practice and be widely available. Other available fertility preservation methods should be considered investigational and be performed in centers with the necessary expertise.52 National funding bodies are strongly encouraged to fund the development of a small network of research-based egg and ovarian tissue storage facilities that will be able to provide universal access to techniques that aim to preserve fertility. With increased awareness among pediatric oncologists and reproductive medicine specialists of fertility issues in young patients with cancer, it is important that an evidence-based approach to the management of the small number of young patients requiring these techniques is developed as a matter of urgency.53

FUNDING SOURCES

Funding for the national task force on adolescents and young adults with cancer has been made possible by a financial contribution from Health Canada through the Canadian Partnership Against Cancer. Funding for the workshop was provided by C17; the Advisory Board of the Institute for Cancer Research at the Canadian Institutes for Health Research (CIHR); the Public Health Agency of Canada; the Ontario Institute for Cancer Research; the Meetings, Planning and Dissemination Grants program of the CIHR; the Terry Fox Research Institute; LIVESTRONG, formerly the Lance Armstrong Foundation; the Canadian Cancer Society Research Institute; Young Adult Cancer Canada; Hope and Cope; and the Comprehensive Cancer Centre at the Hospital for Sick Children, Toronto, in addition to the support provided by the Canadian Partnership Against Cancer to the Task Force on adolescents and young adults with cancer.

CONFLICT OF INTEREST DISCLOSURES

The author made no disclosures.

Ancillary