Abstract
Post-pubertal males with cancer who are exposed to certain chemotherapy agents, radiation therapy to gonadal tissue, or surgery on reproductive organs are at risk of permanent infertility due to depletion of spermatogonial stem cells or irreversible sexual dysfunction. Pre-treatment sperm banking is an established fertility preservation (FP) method. 1 Many organizations including the American Society of Clinical Oncology, American Society for Reproductive Medicine, Association of Pediatric Hematology/Oncology Nurses, National Comprehensive Cancer Network, and the International Guideline Harmonization Group, recommend that infertility risk be discussed with post-pubertal males at diagnosis, and that a referral to discuss sperm banking be offered before treatment initiation.1–5
Despite being an established and effective FP method, sperm banking is vastly underutilized in post-pubertal adolescent and young adult (AYA) males with cancer, leading to psychosocial distress and regret about missed FP opportunities among survivors.6,7 In the 2022 landscape survey of the
Historically, infertility risk stratification has been used at cancer diagnosis to guide discussions about potential fertility outcomes and the need for sperm banking. 11 Under this paradigm, individuals receiving high-risk therapies would be encouraged to bank while those intended to receive low-risk therapy would not. However, this approach does not reflect a complete understanding of infertility risk. First, males undergoing treatments that are generally considered low risk (e.g., non-alkylating agent chemotherapy or radical orchiectomy) may still bear a risk of permanent azoospermia. 12 Second, while a subset of high-risk exposures reliably correlates to a high risk of permanent azoospermia, a much larger group of chemotherapy agents and lower dose scatter from non-testicular radiation can transiently interrupt the sperm maturation process and function.13,14 This temporary azoospermia can last months-years, limiting reproductive autonomy in males who wish to sire children prior to the resumption of normal sperm maturation. 13 Likewise, if this desire for fertility occurs during the spermatogenic cycles immediately following initial treatment, the quality of sperm banked between treatments may be compromised. 15 Third, therapy with a higher risk for infertility may become necessary in those who don’t respond to first-line therapy or relapse, with the inability to bank during the period of temporary azoospermia. 16 Fourth, even if gonadotoxic exposures do not result in azoospermia, there may be long-term effects on bulk semen parameters and sperm quality that have the potential to impact pathways to pregnancy and health of offspring. 13 Lastly, newer treatments such as immunotherapeutic agents have unclear gonadotoxic risk profiles, further complicating the risk-stratification process. 11
Do these scenarios justify a recommendation that all post-pubertal males should bank sperm prior to cancer treatment regardless of the initial risk-stratification? To address this question, we must consider the risks associated with sperm banking, both medical and financial.
The medical risks associated with pre-treatment sperm banking are low. When accomplished via masturbation, sperm banking is noninvasive and can be completed expeditiously with minimal treatment delays. While there may be mild discomfort or psychological distress for some AYAs asked to produce a sample for cryopreservation, this is likely transient. Beyond the specimen collection itself, there is robust evidence to support the safety and efficacy of long-term sperm cryostorage, such that males who cryopreserve can be reassured regarding safety and future family building options, which is a psychosocial benefit.17,18
While the medical risks are minimal, financial costs of FP can be substantial in the United States. Most insurance policies exclude FP procedures as part of comprehensive cancer care. 19 However, compared to oocyte and embryo freezing, which can cost up to $15,000–20,000, sperm banking is much less expensive; initial analysis, processing and one year of storage cost approximately $600–800 per year. Annual storage fees are approximately an additional $250–400 per year and are usually not covered by insurance even in states that have insurance mandates. 19
To alleviate the cost of unnecessary long-term storage, males can undergo a semen analysis following treatment completion to assess whether they have retained/resumed the capacity for sperm maturation. Guidelines recommend waiting approximately 12 months to obtain a semen analysis following treatment completion. 20 Males with azoospermia at initial post-treatment testing can continue future testing given that the resumption of sperm maturation can be variable. 20 Males with return of sperm to the ejaculate should consult with their multi-disciplinary health care team (e.g., oncologist, reproductive specialist) prior to discarding any samples, to address risks such as severe oligospermia, DNA fragmentation issues, and risk of relapse. In cases where the patient/family is behind on payments, the storage facility should reach out to both the patient/family and the health care team before discarding samples, as the health care team may be able to offer financial assistance.
In sum, given the favorable benefit-to-risk ratio, all post-pubertal AYA males with cancer should have access to sperm banking before treatment begins. Structural barriers need to be mitigated to facilitate banking. 21 Ongoing advocacy is needed to alleviate the financial costs of sperm banking and minimize disparities in access to fertility care. 19
Sperm Banking When Masturbation Is Not Possible
Some individuals may not be able/willing to produce a semen sample via masturbation (e.g., due to severe illness, neurological conditions precluding ejaculation, or cultural/religious objections). 21 Adolescents may also face challenges due to early pubertal development and/or sexual inexperience—information that should be obtained in a brief, confidential portion of the consult with the adolescent. 21 Alternative collection methods could then be considered, including testicular sperm extraction (TESE) or electroejaculation (or micro-TESE if the patient is azoospermic), though these options have a different risk profile than masturbation and are not universally available. 21
Sperm Banking After Initiation of Gonadotoxic Treatment
The strong recommendation for sperm banking prior to gonadotoxic therapy is based on concerns that chemotherapy and radiation can impact the quality of sperm banked.6,13 Unfortunately, in the COG survey, nearly one-third (29%) of institutions offered banking after treatment initiation. 9 Patient, clinician, and system level barriers can all contribute to delays in banking. Patients may have insufficient time to secure financial resources and/or complete banking due to illness severity before treatment. Some clinicians report difficulty accessing their local sperm banks due to distance and/or limited hours; research has also shown that some clinicians lack knowledge and confidence about individual risk. 21 We hypothesize that the over-emphasis on risk-stratification for post-pubertal males leads to missed opportunities for pre-treatment banking, both due to burdening clinicians with calculating the risk and due to an inaccurate assessment of risk for patients who ultimately require more gonadotoxic therapy.
Regardless of the reason for delay, post-treatment sperm banking requires thoughtful consideration and nuanced counseling. Beyond the possibility that a patient may already be azoospermic during this post-treatment window, 20 there are concerns regarding the potential impact of gonadotoxic therapies on sperm quality and DNA damage, which may impact pregnancies and future offspring if these sperm are used for family building. 15 As such some sperm banks have policies against banking within 3–6 months of chemotherapy exposure whereas others allow banking and leave the counseling to the provider. 16 Given this variability, we recommend that clinicians use an informed consent model, acknowledging the possible risks of impaired sperm quality/DNA damage which can result in birth defects in future offspring when banking is done after exposures have occurred. 15 This counseling should be documented in both the patient’s medical record and with the semen sample (often located in an outside facility), so that the information is available upon sample retrieval. Ultimately, further collaborative research efforts are needed to better characterize the risks of sperm cryopreservation in the post-chemotherapy setting, specifically addressing the outcomes of assisted reproductive technologies and health of offspring conceived using chemotherapy-exposed sperm. 15
Conclusion
In summary, given the low medical risks and the various pathways towards mitigating financial costs of sperm banking, we recommend universal FP consultation for all post-pubertal males, regardless of the infertility risk stratification, at the time of their initial diagnosis and treatment planning. Pre-treatment sperm banking should be recommended as a standard of care FP option to all post-pubertal males diagnosed with cancer across all treatment settings. Barriers to banking need to be mitigated at the system, clinician, and patient/family level. Ongoing efforts are needed at the system level to institute policies and mechanisms to avoid missed opportunities for FP consultation (e.g., opt-out consult orders in the electronic medical record); 22 increase staffing to deliver timely fertility counseling and facilitate sperm banking; and alleviate financial toxicities associated with FP. 19 Alternatives such as mail-in sperm cryopreservation may expand future opportunities for banking for those with limited access to local sperm banks. 23 Finally, given the evidence that providers and family members influence AYA banking decisions, 24 clinical teams should facilitate family-centered communication and decision-making to increase pre-treatment banking rates and optimize long-term reproductive and psychosocial outcomes. 25
Footnotes
Authors’ Contributions
L.N.: Conceptualization, writing—original draft preparation. J.A.H.: Conceptualization, writing—reviewing and editing. K.B.: Writing—reviewing and editing. O.F.: Writing—reviewing and editing. K.O.: Writing—reviewing and editing. J.R.: Writing—reviewing and editing. J.F.S.: Writing—reviewing and editing. T.W.: Writing—reviewing and editing. J.L.: Conceptualization, writing—original draft preparation, supervision.
Author Disclosure Statement
Dr. Halpern is an employee of Posterity Health; Dr. Smith is an employee of Fellow Health. None of the other authors have conflicts to report.
Funding Information
Dr. Nahata has received funding from the NIH/NCI (5K08CA237338-05).