Adolescent
Emotional
• Transition from abstract to concrete thinking
• Creation of self-identity
• Development of sexual preferences
Physical
• Physical development affects capacity to bank sperm
Psychosocial
• Less concern with the future, may not be thinking about parenting
• Various degrees of knowledge about masturbation
Ethical
• Parents/guardians make decisions for minors
• Adolescent’s decision may be different than parent/guardian
• Adolescent’s notions about masturbation may conflict with familial values
Legal
• Adolescent’s ability to provide assent but not consent
• Disposition of cryopreserve sperm or tissue in future
Financial
• Adolescents are dependent on guardian/parent to pay for fertility preservation
Cancer-Related Risks for Male Infertility
Evaluations of male patients have demonstrated that diminished fertility or infertility can exist at the time of a cancer diagnosis prior to treatment [14, 15]. Testicular cancer is known to be associated with pretreatment decreased sperm concentration, motility, and total sperm count [16]. A recent assessment by Paoli et al. identified impaired spermatogenesis in 25% of adolescent and young adult males diagnosed with Hodgkin lymphoma at the time of diagnosis [17]. In addition, constitutional symptoms such as fever and anorexia have been associated with impaired semen parameters [18, 19]. Cancer-directed therapies can permanently affect male fertility by damaging self-renewing spermatogonial stem cells. Among chemotherapy agents , alkylators, including cyclophosphamide, ifosfamide, procarbazine, melphalan, and busulfan, consistently exert the most deleterious effect on male fertility, in a dose-dependent fashion. For example, a total cumulative dose of 19 g/m2 of cyclophosphamide consistently results in azoospermia, while abnormal semen parameters are seen after exposure to a total cumulative dose of 5–7.5 g/m2 and impaired spermatogenesis is unlikely with a cumulative dose less than 4000 mg/m2 [20–25]. These agents are commonly used as the backbone of therapy for lymphomas, sarcomas, and germ cell tumors and as conditioning for stem cell transplants. Additionally, the use of multiple alkylating agents in a single regimen results in an additive effect on gonadal toxicity.
Radiotherapy to the spinal or pelvic regions , as well as whole-body irradiation, can also impair fertility. The extent to which the testis is affected is dependent on the dose, fractionation schedule, and field. The testicular germinal epithelium is highly sensitive to radiation. Doses of radiation to the testicles at 0.1 Gy can impair spermatogenesis, with irreversible damage after a single testicular dose exceeding 4–6 Gy. Small fractions of testicular radiation over time are more detrimental than an equivalent single-dose exposure. Patients with central nervous system malignancies who undergo cranial irradiation, typically at doses of 30 Gy, may also be infertile due to disruption of the hypothalamic-pituitary-gonadal axis [24]. The effects of surgical intervention on male fertility are related to the removal of male reproductive organs and nearby structures that are also vital to reproduction [26]. Some testicular malignancies, i.e., testicular rhabdomyosarcoma, involve retroperitoneal surgeries such as lymph node dissection, which may damage the nerves responsible for ejaculation [18, 27]. Immunotherapy is now becoming an integral part of cancer therapy for many malignancies, but data is scant on the effect of immunotherapy on male fertility and further studies are needed to monitor the effects of these therapies in the long term [11].
Sperm Banking in Male Adolescents
Sperm banking via masturbation at diagnosis is the standard-of-care fertility preservation method for postpubertal cancer patients whose treatment-related exposures place them at high risk of permanent azoospermia post-therapy [28, 29]. Current recommendations also suggest consideration of sperm banking for all postpubertal males, regardless of risk [30]. The rationale for this recommendation is based on the fact that exposure to chemotherapy with a low risk for permanent azoospermia can still cause temporary azoospermia . This temporary azoospermia may preclude the opportunity for males to sperm bank in the setting of relapse where a patient may be exposed to additional gonadotoxic therapy, and consequently permanent azoospermia. While the primary recommendation for sperm banking via masturbation is the same in the adolescent and adult population, the process of introducing and accomplishing sperm banking in the adolescent patient introduces very different challenges, particularly in younger adolescents.
Factors Affecting Capacity to Sperm Bank
An initial aspect of fertility preservation with adolescent males is an assessment of the patient’s pubertal status and capacity to bank sperm. Capacity refers to the individual’s ability to intellectually understand the implications of fertility preservation as well as physically provide sperm.
The period of adolescence is marked by rapid psychosocial growth, development of identity, and formation of sexuality. The beginning of adolescence is further characterized by the developmental transition from concrete to abstract thinking. For adolescents in the concrete thinking phase, it may be challenging for them to contemplate making decisions about matters such as maintaining the opportunity for future parenthood [31]. One case series showed that young men rejected the idea of sperm banking based on a common adolescent feeling of invincibility, believing that they would either not become infertile or would not care if they did. This was accompanied by regret later on in life [32]. Klosky et al. examined future fertility as a priority for adolescents at diagnosis and found that only half of those adolescents surveyed reported having children as a top life priority [33].
Emotional development, physical maturity, and the current state of illness all impact an individual adolescent’s ability to produce sperm for cryopreservation. Concepts such as sexuality, reproduction, and masturbation may not have been previously discussed within the family unit and may be embarrassing to the patient [5]. Raising these issues to maintain fertility may exacerbate stress and anxiety and impact the ability to masturbate. Indeed, depending on the patient’s age, one should expect varying levels of knowledge and experience with masturbation and ejaculation; a thorough history should elicit this information from the adolescent. The physical exam must evaluate development of secondary sexual characteristics, including testicular volume, penile size, and pubic and axillary hair. In order to masturbate to ejaculation, a patient generally needs to be Tanner stage III or higher [18, 34, 35]. Finally, even in a patient who is emotionally and physically mature enough for sperm banking, the patient’s state of illness, including any underlying pain, physical discomfort, immobility, or critical state due to the underlying malignancy, may hinder their capacity to masturbate.
Initiating the Discussion and Decision Making
A new diagnosis of cancer presents an extremely stressful situation for an adolescent and his family. In addition to facing the prospect of a life-threatening illness, the patient and his family are often exposed to a whirlwind of logistics involved in diagnostic tests and the establishment of a treatment plan. Very often, the window for fertility preservation is small due to the pressing need to start cancer therapy. This presents added pressure for introducing the risks cancer treatment poses to future fertility and the options for fertility preservation. A thoughtful introduction of sperm banking must acknowledge the stress of the situation as well as the factors for capacity outlined above. While the initiation of the topic of fertility and sperm banking presents unique challenges in this setting, it is also a topic about which patients and families want information and which they may already have concerns [34, 36].
Because of potential time constraints, the topic of fertility preservation may need to be raised while diagnostic procedures and treatment planning are still under way. Preferably, the introduction of the infertility risks and fertility preservation options is initiated with the patient and his parents together although, depending on an assessment of family dynamics, there may be consideration of presenting this information separately [5]. Ideally, there should be an opportunity for the patient to speak privately with the physician and medical care team as he may feel uncomfortable discussing masturbation with a parent or guardian present. Patients may also have concerns about their own sexuality and gender identity which may or may not overlap with their own and/or their families’ religious beliefs and culture, which may prohibit masturbation. In addition, parents may be incorrect in their assumptions about whether or not their child is able to masturbate [37]. During this conversation, the child can decide who they would like present in the room when making fertility preservation decisions and when receiving information about the actual process. Crawshaw et al. identified that almost half of patients preferred to have the initial discussions without their parents present, but were pleased with their parents’ role in the decision-making process [5, 38]. Ginsberg et al. found 58.3% of adolescent cancer patients and 79.5% of parents reporting that the decision to bank (or not bank) sperm was made conjointly [34]. In addition, the role of parents must account for logistical aspects of the process, including payment, communication with the medical team, and making arrangements with the sperm banking clinic [39]. Studies have found that the single most important reason for undergoing fertility preservation was a desire for children in the future [35]. Reasons for declining sperm banking were fears of delaying therapy and worries about the consequences of children conceived from frozen sperm [40].
Logistical Issues
Explaining the Process
An explicit and detailed explanation of the sperm collection process should be provided to the adolescent. As stated above, it is important to clearly assess the patient’s knowledge and experience with masturbation, including establishing that the patient understands what is meant by masturbation, as they may be more familiar with alternative terms. The discussion should include what types of age-appropriate stimulatory materials, e.g., magazines or videos, have been used by the patient in the past and whether they believe the presence of such materials will be necessary in the current situation. At the time of sperm collection, that patient should be instructed to wash and dry hands, and then masturbate to ejaculation into a sterile cup. It is important to advise patients that they cannot use saliva or lubricants to masturbate since this may impact sperm quality, although mineral oil limited to the shaft of the penis can be used. If it is feasible to delay the start of therapy, patients should be directed to masturbate to ejaculation and then abstain from ejaculation for 48 h prior to sperm collection.
It is also important to let the adolescent know that they may not succeed in masturbation and/or ejaculation and provide reassurance if this were to occur. Informing them that pain and illness may be contributing to their inability to do so may also help. It is important to reinforce that they should not be embarrassed or distressed if they are not successful. In addition, it is possible that, even if they successfully ejaculate, there may be no viable sperm and that this may be related either to age, disease, or occasionally underlying conditions, such as Klinefelter’s [41, 42]. Providing them with knowledge about alternate methods may also alleviate the stress associated with the process.
Establishing a Safe Space
It is critical that the patient have a private space wherever sperm banking is attempted. When patients must remain admitted to the hospital, a designated room should be identified if they are not in a single room. All curtains should be pulled down and doors covered. When possible, doors should be locked and “Do not disturb” signs can be hung to ensure privacy. A member of the medical team can be designated to remain outside the door and prevent interruptions.
It is equally as important to ensure the patients’ comfort if they are outpatient and it is possible for them to go to a sperm banking facility. When possible, institutions should establish relationships with sperm banks that are experienced with adolescents, as well as oncology patients. When these relationships do not exist it is incumbent upon the medical practitioners to alert the sperm banking facility about the patient’s age and reason for sperm banking. When personnel are knowledgeable about this group, they can provide more sensitive and personalized care and can prevent a great deal of embarrassment for the patient. Patients should be advised that they will be given a small private room for the collection. If feasible, parents and practitioners should allow the adolescent to choose who they want to accompany them to the sperm bank. One study suggested that adolescent boys may be more successful at masturbation if a parent does not accompany them to the sperm bank [29, 43].
Demonstrations of Success
A recent large (N = 4345) retrospective study of the French national sperm banking network demonstrated a 93% success rate for providing a sperm sample by masturbation among a population of primarily newly diagnosed adolescent oncology patients, median age 18 years. Of this group 83% had sperm frozen; reasons for not being able to freeze sperm included very small semen volume, low motility, and oligo- or azoospermia. Increases in age were associated with greater success, 81% in 11–14-year-old age group vs. 95% in 18–20-year-old age group [42]. In a smaller but similar study from the UK with a slightly younger population (mean age 16.1 years), 66% of subjects successfully banked sperm, 10% were unable to provide a sample, and 13% had an ejaculate that did not contain sperm. Semen volume and number of ampules stored increased with an increase of age; there was no difference in parameters based on disease type [44]. Edge et al. showed that those who were unsuccessful in fertility preservation were younger males and those who described more anxiety at diagnosis. They had greater difficulty in talking about fertility and less understanding of the process [41, 45]. It should be noted that patients as young as age 12–13 successfully provide sperm samples via masturbation, suggesting that age itself does not preclude the capacity to sperm bank [46–48].
Alternate Methods for Sperm Collection
If masturbation is not possible, alternate options exist for obtaining sperm. Electroejaculation (EEJ ) involves electrical stimulation using a transrectal probe to trigger ejaculation and collection of sperm. Other methods include microsurgical epididymal sperm aspiration or testicular sperm extraction (TESE ). These methods can also be used when sperm counts are low or in the case of obstructive azoospermia. Disadvantages to these procedures are that they require general anesthesia and are invasive, although they can be combined with other necessary procedures (i.e., placement of central line) that also require sedation [35]. These methods may be particularly applicable for younger adolescents who may have greater difficulty producing sperm [42, 49].
An alternate experimental method involves cryopreserving testicular tissue prior to exposure to cancer therapy. This is done with the goal of later germ cell transplantation into the patient’s own testes or matured in vitro and used in conjunction with intracytoplasmic sperm injection (ICSI ) to fertilize an embryo [50]. This is the only option that is available for prepubertal males as they do not produce mature spermatozoa. As an experimental methodology this intervention should only be offered under an IRB-approved protocol. Ginsberg et al. have identified that parents are willing to participate in this experimental procedure. Those who consented to the procedure endorsed beliefs that scientific advances in reproductive medicine would be successful in using the testicular tissue. They also felt that fertility was important and worth trying to preserve. These parents also reported wanting to mitigate the potential psychological trauma of infertility due to cancer therapy. After the procedure was completed, all families felt that they had made the correct decision for their child. Those who declined the procedure did so over concerns with the risk of biopsy. They were also more overwhelmed at the time of decision. The experimental nature of the procedure was not a factor for those who consented or refused the procedure. Interestingly, neither group stated that their decision was significantly influenced by religion, ethics, or finances. This was supported by data that showed no significant differences between those who consented or refused in relation to any of these factors [30].
Ethical and Legal Issues
In the young adult population, ethical and legal issues in the setting of fertility preservation are related to the disposition of cryopreserved gametes in the event of patient death and the use of cryopreserved embryos either in death or dissolution of a relationship. Because adolescents have not yet reached the age of majority and consequently are not able to consent to procedures, additional ethical and legal issues can arise. In most circumstances, unless they are emancipated, parents or legal guardians are making the majority of the medical decisions for their children [10]. Many adolescents do have a clear understanding of the issues related to fertility preservation and may wish to voice their reproductive choice. These choices may contradict their parents’ wishes and pose a dilemma for families and practitioners [5]. This conflict can arise in the setting of religious beliefs especially when there is prohibition against masturbation. While both points of view should be respected, it is also important to acknowledge that the child’s religious views may differ or change with time [29, 51]. When conflicts arise the assistance of a child psychologist or psychiatrist may also aid in the process, both in understanding the child’s level of comprehension about sexual reproductions and helping with the assent process [51].
Testicular tissue cryopreservation presents especially controversial issues if there is disagreement between parent and child about undergoing the procedure because it is invasive and experimental, with a need for anesthesia. While the decision about harvesting immature germ cells may be made by a parent or guardian, the decision of how to use the gametes in future should be made by the patient at the time of adulthood [51]. The disposition of cryopreserved sperm or tissue must also be addressed at the time of cryopreservation. For adolescents, the sperm or tissue must either be discarded or designated for research if death were to occur. It is deemed unethical to use children’s cryopreserved sperm for posthumous reproduction [18]. At the time of attaining majority, the contract related to sperm disposition must be re-addressed if this was not clearly articulated in the original contract.
Financial Issues
The average cost of sperm banking in the United States has been reported as a range from $1000 to $1500 for analysis, freezing, and the initial year of storage, plus $300–$500 per year for additional years of storage [18, 29, 52]. The average cost of testicular sperm extraction is $6000–$16000 [52]. The wide range in cost is attributable to various factors, including hospital fees, anesthesia, and equipment, and likely varies with region. The younger the patient is at the time of sperm collection generally translates into a longer time frame in which they need to pay for the annual storage of sperm, thereby increasing the overall cost. Compounding these expenses is the utilization of sperm at the time of desired conception when the adolescent reaches adulthood. This includes fees for thawing sperm. The cost of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) may be more than $20,000 [18, 53]. To minimize cost, it is reasonable to consider performing a semen analysis following the time period of greatest risk for relapse to assess fertility and to consider disposing of cryopreserved sperm in the setting of normal sperm production. Although considered a standard of supportive care, many healthcare insurance policies do not provide coverage for fertility preservation costs for patients with an oncologic diagnosis leading to inequitable access to care.
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