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The number of pediatric cancer survivors is growing rapidly as treatments become more effective. However, many current regimens cause gonadotoxicity and permanent infertility, significantly impacting quality of life. The purpose of this review is to update pediatric oncologists on risk factors for cancer treatment-associated gonadotoxicity, current methods for fertility preservation and new scientific advances in this area.
Infertility is an enormous quality of life issue for pediatric cancer survivors and their families. Numerous treatment options are already available to prevent infertility in patients at risk. It is important to counsel patients at risk and initiate management for fertility preservation prior to beginning therapy. Preclinical research indicates that it may be possible to bank gonadal tissues from patients for subsequent re-implantation after therapy or expansion of germ cells in vitro. Further translational studies are required to advance these technologies into clinical use.
Pediatric cancer survivors are at risk for long-term treatment-related gonadal failure and infertility. Counseling and treatment should begin prior to initiating chemo or radiation therapy. Recent scientific advances in understanding germ cell biology should eventually generate new clinical strategies to maintain fertility in pediatric cancer patients.
Survival rates for childhood cancer are steadily increasing. Remarkably, overall cure rates for pediatric malignancies now approach 80% (1). However, gonadal damage is a relatively common consequence of pediatric cancer treatments (2, 3). As outcomes have improved, more survivors are entering their reproductive years. For these patients, fertility maintenance maximizes long-term quality of life (4). Thus, it is essential for pediatric oncologists to consider the potential impacts of treatment on every patient’s fertility. It is critical that this occurs prior to initiation of gonadotoxic therapy, when a window of opportunity may exist to preserve future reproductive potential. This article reviews the gonadotoxicity of pediatric cancer therapies, current fertility preservation options for pediatric patients and new scientific advances that are likely to benefit future patients.
Recent estimates indicate that 1 in 1,300 young American males is a survivor of childhood cancer (1). Approximately 30% of these individuals received gonadotoxic treatment, resulting in permanent infertility (5). Accordingly, nearly 1 in every 5,000 young males is at risk for infertility from pediatric cancer treatment. Unfortunately, male germ cells are particularly susceptible to injury by cytotoxic drugs and radiation therapy. The spermatozoa-producing germ cells are more sensitive to chemotherapy and radiation compared to the testosterone-producing Leydig cells (6). Therefore infertility is more often a late effect of cancer therapy in males, while sexual function is relatively spared.
Testicular dysfunction ranks as one of the most common long-term side effects of chemotherapy in males. High mitotic rates render the germinal epithelium exquisitely susceptible to injury by cytotoxic drugs, particularly alkylating agents (7, 8). The extent and reversibility of cytotoxic damage generally depends on the specific drug and the cumulative dose received (3). Alkylating agents most commonly associated with infertility include cyclophosphamide, ifosfamide, procarbazine, busulfan and cisplatin (Table 1) (3, 9–11). The total cumulative dose of gondatoxic drug correlates with the potential for damage to sperm forming cells. Moreover, the vast majority of pediatric cancer patients are given multiple chemotherapeutic drugs as part of their treatment. Infertility may result at lower total doses of individual alkylating agents due to synergistic gonadotoxicity associated with multi-drug regimens.
The spermatogenic capacity of the testes can be suppressed by extraordinarily low doses of radiation. As little as 10–20 centi-Gray units (cGy) of scattered radiation in a fractionated regimen can cause transient oligospermia. Permanent (or at least very long-term) azoospermia can occur after 140 – 260 cGy of fractionated scatter radiation (12). Notably, irradiation doses used for the treatment of testicular acute lymphoblastic leukemia (ALL) exceed this limit by approximately tenfold (1200–2400 cGy) and are expected to cause permanent azoospermia in virtually all male patients (13). Total body irradiation (1200 cGy) used for some hematopoietic stem cell transplantation conditioning regimens also delivers sufficient testicular radiation to cause permanent infertility (14).
Cryopreservation of sperm is now standard practice. Parents and patients frequently request information on this topic early in their treatment program, before chemotherapy begins (16). Some clinicians advocate sperm banking only for males who are at high risk for treatment-induced infertility. However, we recommend universal sperm banking for all males at Tanner stage III and above with newly diagnosed malignancies, regardless of planned treatment intensity. This approach maximizes fertility options for patients who might relapse prior to sperm count recovery and therefore face more gonadotoxic chemotherapy. It is important to bank sperm prior to initiating chemotherapy, as even small doses gonadotoxic agents can affect the quality of the frozen specimen (16–18).
Viable sperm can be collected successfully from most adolescents and young adults with newly diagnosed cancer. The least invasive method for sperm collection is masturbation, although several other approaches are available if this is not possible. These include microsurgical epididymal sperm aspiration, whereby sperm is removed from the epididymal tubule and testicular sperm extraction, which is performed via a needle biopsy of the testes (19). Numerous recent improvements in sperm storage techniques and advances in assisted reproductive technology using intracytoplasmic sperm injection (ICSI) facilitate successful pregnancies using banked sperm, which is documented to remain viable for up to 28 years, if stored properly (15).
Prepubertal males pose a challenge for fertility maintenance because these patients cannot produce semen for cryopreservation. Although germ cells of the prepubertal testis include spermatogonial stem cells (SSCs), mature spermatozoa are not yet present. However, it should be possible to cryopreserve patient testicular tissue for eventual restoration of spermatozoa production after completion of cancer treatment. Significant scientific advances in SSC biology, including successful animal models for regeneration of male fertility, should eventually benefit patients (20, 21). For example in murine models, spermatogonial transplantation restores spermatogenesis and reproductive capacity (23, 24). Ideally, prepubertal testicular tissue from patients could be acquired and banked prior to initiating gonadotoxic cancer therapy. Years later, once the patient is ready to begin a family, this tissue could then be thawed and the stored germ cells reimplanted into the patient’s own testes to continue full maturation in situ (22, 23). However, current biopsy specimens contain too few SSCs cells to restore fertility. Moreover, contaminating cancer cells must be detected and removed from testicular biopsy samples. One innovative strategy utilizes in vitro culture methods to expand and purify gonadal SSCs, guide their differentiation into viable spermatids, then achieve fertilization through ICSI. Several hurdles remain for translating fertility-based science into the clinical setting for prepubertal boys with newly diagnosed cancer (Table 2). For example, it is important to maximize the viability of frozen testicular tissue including resident SSCs, determine optimal culture conditions for expansion of human SSCs, and develop methods for in vitro differentiation of human SSCs into spermatids.
Groundbreaking clinical research demonstrates feasibility, acceptability, and safety of testicular tissue cryopreservation for boys with newly diagnosed cancer. At the Children’s Hospital of Philadelphia (CHOP) 24 of 29 parents of eligible prepubertal boys consented to testicular tissue cryopreservation. Testicular biopsies were performed prior to initiation of cancer therapy, when patients were under anesthesia for another procedure, such as central line placement or tumor biopsy. Half of the testicular specimen was frozen for potential future clinical use and the other half was used for spermatogenesis research to address translational hurdles described. There were no complications associated with the procedure (25). Despite the stresses associated with newly diagnosed cancer, parents and patients gave thoughtful consideration to testicular cryopreservation. A questionnaire administered at the time of consent for testicular tissue banking indicated that factors such as religion, finance, ethics, and the experimental nature of the procedure did not play a major role in decision-making (25).
Females have a finite number of ovarian primordial follicles that decrease in number through maturation and atresia during aging. Reproductive potential declines as follicle numbers decrease, ultimately resulting in infertility. Cancer therapy accelerates this natural decline in follicles. Both chemotherapy and radiation destroy ovarian follicles and predispose females to premature ovarian failure (26, 27). The effect of chemotherapy depends on the age of the patient at treatment, the type of chemotherapy administered, and the total cumulative dose of drugs (28). Similar to males, alklyators are the most potent gonadotoxic agents (29). Gonadotoxicity in females is age-dependent, with older women being more susceptible, as there is an overall smaller follicular pool during therapy. For instance, the same cancer treatment regimen is more likely to cause infertility in a 30- or 40-year-old woman compared to an adolescent or young girl. In contrast to male patients, a much higher dose of drug is required to cause infertility in females. In regards to the pediatric patient, females are more likely to be at risk for long-term premature ovarian failure rather than acute ovarian failure. Thus, a female pediatric cancer patient is more likely to have a window of fertility after completion of treatment, although alkylating agents may reduce her overall fertility span. Pelvic irradiation can also permanently damage the ovaries. Doses as low at 400–600 cGy in adults and 1000–2000 cGy in children can decrease ovarian function (30, 31). Ovarian damage can be lessened if the ovaries are surgically displaced from the radiation field prior to therapy. Unfortunately, female patients who receive a stem cell transplant with total body irradiation are at greatest risk of developing permanent ovarian failure (32). Moreover, the adverse effect of radiation on ovarian function is compounded if with concomitant alkylator chemotherapy (33). In this situation, ovarian dysfunction may occur despite the use of low doses of radiation.
The most well established option for female fertility preservation is embryo cryopreservation. This method allows the patient to undergo ovarian stimulation for the in vivo maturation of oocytes and subsequent retrieval of mature oocytes prior to beginning chemotherapy. The oocytes are then fertilized when they are retrieved and the resultant embryo is cryopreserved. Years later, the embryo can be thawed and transferred into either the patient’s own uterus or that of another women (gestational surrogate). Unfortunately, in the pediatric setting, this is not a feasible option since it requires ovarian stimulation that may not be possible due to time constraints, or appropriate in prepubertal patients (34). Additionally, embryo cryopreservation requires the use of a partner or donor’s sperm, which is not necessarily possible for single teenage females (19). Embryo cryopreservation is possible if the single young female is willing to use donor sperm and may be most appropriate in the young adult facing a stem cell transplant. The pregnancy rate with this technique averages 30–40%.
Oocyte cryopreservation is an alternative means of gamete storage that may appeal to young women not in an established relationship. Oocyte cryopreservation is a developing technology for females who wish to preserve fertility but do not have a partner and who do not wish to use donor sperm. Oocytes are very fragile and difficult to cryopreserve, with consequent low viability after thawing (35), although successful pregnancies have been obtained using this method and the technology is improving (36). There are limitations for the pediatric patient, however, as oocyte cryopreservation requires ovarian stimulation. Thus, the feasibility of accomplishing this procedure prior to beginning chemotherapeutic therapy in the pediatric setting is unlikely due to time constraints and overall invasiveness of the procedure (34). Furthermore, ovarian stimulation is inappropriate in prepubertal girls as it initiates puberty.
Overall, embryo and oocyte cryopreservation have been successful, although embryo cryopreservation currently has a higher success rate. Unfortunately, neither of these options are currently feasible for a newly diagnosed pediatric cancer patient (19). Long-term approaches include modifying cancer treatment regimens to maintain female fertility without compromising efficacy, and use of ovarian biopsies for reimplantation or in vitro derivation of oocytes, similar to what is now being explored for males.
Ovarian tissue cryopreservation is a proposed fertility option for pediatric cancer survivors, as this allows for the long-term storage of large numbers of primordial follicles. This represents the only potential option available to preserve fertility in prepubertal girls or pubertal girls who cannot delay their cancer treatment (21, 34). The method involves freezing ovarian cortex segments for subsequent thawing and transplanting either back to the ovary or to some other location. The cortex is utilized because it is rich in primordial follicles (37). The stored ovarian tissue could then theoretically be reimplanted, or immature oocytes could be harvested and matured entirely in vitro. In vitro maturation is more appealing, as it would remove the danger of reimplanting cancer cells back into the patient. Methods of growing human oocytes from primordial follicles are the focus of intense laboratory investigation (38). Ovarian transplantation might be most concerning in patients with blood borne malignancies, where contaminating cancer cells theoretically seed ovarian tissue (19, 39).
Ovarian cryopreservation and reimplantation has been successful in approximately a dozen reported cases and is appropriately considered to remain experimental (40). Furthermore, recent evidence illustrates the potential risks of reimplanting tissue contaminated with cancer (39). Because of the invasive nature of an ovarian biopsy and its experimental nature, this option should only be considered for consenting females who are at high risk for treatment related acute ovarian failure (Table 2). Based upon these criteria, the most appropriate candidate is a female facing bone marrow transplantation, which can be particularly gonadotoxic. In contrast, many other pediatric patients who may be exposed to high doses of alkylator therapy will often have a window of fertility following their treatment, as they are more likely to be at risk for long-term premature ovarian failure. This group of patients is more likely to benefit from currently available fertility preservation options such as embryo or follicle cryopreservation in young adulthood after recovery from cancer.
Pediatric cancer therapy has improved greatly over the last several decades with survival rates approaching 80%. Now, more than ever, it is critical that we address the quality of the lives saved. Fertility is a quality of life issue of great importance to cancer survivors and must be addressed prospectively, before treatment is initiated. Fertility preservation options for the pediatric cancer patient differ from those in adults due to differential toxicities of treatment regimens and relative immaturity of pediatric germ cells. Basic science research on germ cell biology promises new advances in fertility preservation, but additional resources and translational studies are required to advance these findings into the clinic. We must continue to develop methods for preserving fertility while treating and curing pediatric cancer.
This work was supported by NICHD grant HD 061217.
There are no financial interests to disclose.