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The current concepts, recommendations, and principles of sperm banking as it pertains to the comprehensive care of young men of reproductive age with cancer are reviewed. Obstacles to sperm banking are addressed as well as future directions for fertility-preserving technologies. All cancer therapies—chemotherapy, radiation, and surgery—are potential threats to a man’s reproductive potential. In addition, cancer itself can impair spermatogenesis. Thus, sperm cryopreservation prior to initiating life-saving cancer treatment offers men and their families the best chance to father biologically related children and should be offered to all men with cancer before treatment. Better patient and provider education, as well as deliberate, coordinated strategies at comprehensive cancer care centers are necessary to make fertility preservation for male cancer patients a priority during pretreatment planning.
Cancer survival rates have improved dramatically over the last couple of decades due to advances in diagnostic techniques and therapies [Agarwal et al. 2004; Lass et al. 2001; McVie, 1999]. Roughly 15% of cases of newly diagnosed cancer in men are in those younger than 55 years of age, and about one quarter of them are younger than age 20 [Steliarova-Foucher et al. 2004]. Consequently, the population of young cancer survivors has grown, and the focus of cancer treatments has shifted from one of survival alone to that of survival and quality of life after treatment.
For many men and their families, the maintenance and preservation of fertility during and after treatment is important [Saito et al. 2005; Mackie et al. 2000; Hartmann et al. 1999; Schover et al. 1999; Rieker et al. 1990, 1989; Gritz et al. 1989]. However, antineoplastic agents, radiation, and surgical therapies can all pose significant threats to a man’s fertility potential, as can the presence of cancer itself. Male infertility due to cancer treatments may be temporary or permanent and can range from mild to severe. Because it is difficult—if not impossible—to predict the exact impact of cancer therapy on an individual man’s ability to father a biological child, sperm cryopreservation prior to therapy remains the cornerstone of fertility preservation in this patient population [Saito et al. 2003; Bahadur et al. 2002b; Kelleher et al. 2001; Agarwal, 2000; Audrins et al. 1999; Lass et al. 1998; Naysmith et al. 1998; Sanger et al. 1992; Fossa et al. 1989]. Unfortunately, in many cases, sperm cryopreservation remains underutilized [Hartmann et al. 1999; Schover et al. 1999; Rieker et al. 1990, 1989].
The causes of poor semen quality in patients with cancer are not well understood, and multiple factors are likely to be involved. Some of these factors include preexisting defects in germ cells, local tumor effects, endocrine disturbances, and autoimmune and systemic effects of cancer [Agarwal and Allamaneni, 2005; Rueffer et al. 2001; Petersen et al. 1999a, 1999b].
A number of studies report that cancer adversely affects semen quality. However, published results of large studies are conflicting. Some suggest that cancer adversely affects semen quality [Colpi et al. 2004; Hallak et al. 1999; Lass et al. 1998] while others have found no differences between semen analyses of men with and without cancer [Rofeim and Gilbert, 2004]. In addition, some studies suggest that the type of malignancy has an impact on semen quality [Williams et al. 2009; Bahadur et al. 2005; Ragni et al. 2003; Lass et al. 1998] whereas others do not [Meseguer et al. 2006; Chung et al. 2004].
Ragni et al. reported that 11.6% of men who wished to cryopreserve sperm at their institution were azoospermic [Ragni et al. 2003]. This ranged from 3.9% of men with non-Hodgkin’s lymphoma to 15.3% of men with testicular tumors. Lass et al. reported that 10.5% of untreated men were azoospermic including 9.6% with testicular tumors, 13.3% with leukemia or lymphoma, and 3.7% of men with other malignancies [Lass et al. 1998]. Colpi et al. reported normal semen parameters according to WHO criteria in only 40% of men with lymphoma, 37% with testicular cancer and 37% with other tumors [Colpi et al. 2004]. Men with Hodgkin’s disease usually present with poor semen parameters [Viviani et al. 1999; Hendry et al. 1983]. Likewise, Lass et al. reported that 50% of men with cancer who cryopreserved at their institution had fewer than 10 million motile sperm per ejaculate [Lass et al. 1998]. Finally, men with testicular cancer had semen parameters that were inferior to those of normal controls [Williams et al. 2009; Hallak et al. 1999]. In contrast, Rofeim and Gilbert compared semen parameters of 214 men with a variety of cancers to 22 men without cancer and found no significant differences between the groups [Rofeim and Gilbert, 2004].
Some studies suggest that the type of malignancy impacts semen quality. A large study of 776 men with cancer demonstrated that sperm density was significantly reduced in men with testicular cancer, but sperm quality did not vary significantly among men with other malignancies [Ragni et al. 2003]. Similarly, a study of 314 patients with cancer found that men with testicular cancer had the lowest pretreatment sperm concentrations compared with those with other malignant neoplasms [Bahadur et al. 2005]. A number of studies have found that men with testicular tumors had significantly lower sperm quality compared with those with hematological or other malignancies [Williams et al. 2009; Hallak et al. 1999; Lass et al. 1998; Berthelsen and Skakkebaek, 1983; Hendry et al. 1983]. Sperm DNA integrity has also been shown to be worse in men with cancer prior to treatment compared with fertile controls [Stahl et al. 2008].
However, there is also evidence to suggest that the type of malignancy does not impact semen quality. Meseguer et al. reviewed semen parameters of 184 men who banked sperm before cancer treatment and found no significant differences in total sperm counts among men with different malignancies [Meseguer et al. 2006]. Likewise, Chung et al. found that sperm counts and motility did not differ by type of cancer in 97 patients who froze sperm before the initiation of cancer therapy [Chung et al. 2004].
Chemotherapy negatively affects spermatogenesis, either transiently or permanently [Howell and Shalet, 2005; Apperley and Reddy, 1995; Spitz, 1948]. These drugs directly damage proliferating cells, so early differentiating sperm cells are exquisitely sensitive to these agents. However, even the relatively quiescent sperm precursors can be damaged due to cumulative effects of multiple doses of chemotherapy [Schrader et al. 2001]. Later-stage germ cells, namely spermatocytes and spermatids, are less sensitive to chemotherapy since they are not dividing, and this accounts for the finding of some sperm immediately following chemotherapy with a slow decline in counts over the ensuing months. Leydig cell function appears to be less affected by chemotherapy.
Improved chemotherapy regimens have resulted in lower rates of infertility, although, azoospermia after treatment continues to be a concern [Meirow and Schenker, 1995]. When men are rendered completely azoospermic after treatment, some report that only 20–50% of these men will have some recovery of spermatogenesis [Carson et al. 1991], while others report up to 80% recovery depending on the type of cancer and chemotherapeutic regimen [Howell and Shalet, 2005].
Alkylating agents including cisplatin are widely used for testicular cancer and have a high risk of azoospermia, particularly when coupled with ifosfamide, and the risk of permanent azoospermia seems to be dose and agent dependent [Howell and Shalet, 2005; Colpi et al. 2004; Leonard et al. 2004; Pont and Albrecht, 1997]. Likewise, most regimens for Hodgkin’s disease also put men at high risk for azoospermia [Viviani et al. 1985]. The impact of newer chemotherapeutic agents such as taxanes and monoclonal antibodies remains unknown [Lee et al. 2006]. Age at treatment may play a role in recovery of spermatogenesis, however this remains unclear [Kenney et al. 2001].
Efforts have been made to explore strategies that may offer protection to the germinal epithelium during cancer therapy. One such approach has been the use of luteinizing hormone-releasing hormone analogs during gonadotoxic therapies have been examined in men. While these medications held promise in some animal studies, they did not significantly protect against spermatogenic failure in humans [Cespedes et al. 1995; Kreuser et al. 1993].
Radiation therapy negatively affects spermatogenesis, either transiently or permanently by directly inducing DNA damage [Apperley and Reddy, 1995; Lushbaugh and Casarett, 1976]. A number of variables can affect the deleterious effect of radiation therapy on gonadal function including total dose, source of radiation, gonadal protection, scatter radiation, and individual susceptibility [Trottmann et al. 2007; Colpi et al. 2004]. Gonadal shielding should be employed routinely; however, a small amount of scatter radiation is inevitable. As little as 0.15 Gy can result in impaired sperm production [Leiper et al. 1986; Speiser et al. 1973]. Doses over 0.5 Gy typically result in reversible azoospermia [Apperley and Reddy, 1995]. Semen parameters often reach their nadir 4–6months after treatment. Doses over 2.5 Gy place men at risk for prolonged or permanent azoospermia [Trottmann et al. 2007; Apperley and Reddy, 1995]. Leydig cell function is affected when doses reach >15 Gy [Howell and Shalet, 2005; Colpi et al. 2004]. Regimens for malignancies such as testicular leukemia and for total body irradiation prior to bone marrow transplants usually result in irreversible damage to the spermatogonia and permanent sterility [Leonard et al. 2004]. Newer radiotherapy strategies may result in less gonadal toxicity but results are pending.
Surgical procedures such as retroperitoneal lymph node dissection (RPLND) in men with testicular cancer can cause infertility as a result of ejaculatory dysfunction due to damage of the pelvic plexus [Fossa et al. 1985]. Both anejaculation and retrograde may result. Modified RPLND templates have been shown to reduce the risk of ejaculatory dysfunction in these men [Large et al. 2009; Donohue, 2003; Hartmann et al. 1999].
While more prevalent in older men, prostate cancer may affect younger men of reproductive age. In addition, many men are waiting until later in life to father children or begin second families. In removing an important male reproductive organ, radical prostatectomy renders these men sterile. Likewise, bilateral orchiectomy and cystectomy can put men at risk for reproductive failure. Low anterior or abdominoperineal approaches to gastrointestinal malignancies may also put men at risk for ejaculatory failure [Jones et al. 2009].
Gonadotoxicity and testicular dysfunction are well-known side effects of cancer therapies since chemotherapy, radiotherapy, and surgery can all affect fertility potential [Giwercman and Petersen, 2000; Naysmith et al. 1998; Jacobsen et al., 1997; Meirow and Schenker, 1995; Carson et al. 1991]. Many men are rendered azoospermic following treatment. Spermatogenesis often returns in these men; however, the timing of the return (ranging from months to years) and the sperm quality when it returns is variable [Spermon et al. 2006; Gandini et al. 2006b; Bahadur et al. 2005; Huyghe et al. 2004]. Approximately 15–30% of childhood cancer survivors are permanently sterile following therapy [Tournaye et al. 1996].
A number of factors may influence the recovery of spermatogenesis following cancer therapy. In addition to the treatment regimen, the individual’s pretreatment fertility potential and the influence of the cancer itself on the man’s overall health can both have an impact on posttreatment fertility [Trottmann et al. 2007; Magelssen et al. 2006]. While the data are somewhat conflicting, certain malignancies, including testicular cancer and Hodgkin’s disease, seem to influence pretreatment fecundity [Williams et al. 2009; Lass et al. 1998].
Among testicular cancer survivors, most were successful in achieving pregnancies, ranging from 71–82%, although successful paternity took many years in some cases and was dependent on the intensity of the chemotherapy or radiation therapy [Brydoy et al. 2005; Huddart et al. 2005; Lampe et al. 1997]. Men with low-stage seminoma rarely become azoospermic after orchiectomy and radiation [Nalesnik et al. 2004; Joos et al. 1997]. High-dose testicular radiation for testicular intraepithelial neoplasia usually results in infertility [Classen et al. 2003].
Survivors of Hodgkin’s lymphoma typically experience azoospermia after treatment. Depending on the chemotherapy and radiotherapy regimens, many patients recover some degree of spermatogenesis, but this may take up to 5–10 years [Tal et al. 2000; Viviani et al. 1999; Marmor and Duyck, 1995; da Cunha et al. 1984]. Non-Hodgkin’s lymphoma regimens seem to be less gonadotoxic than those used to treat Hodgkin’s disease [Howell and Shalet, 2005]. Life-saving bone marrow transplantation strategies can also impair fertility, with azoospermia rates ranging from 10% to 70% depending on the agents, doses, and body irradiation templates employed [Anserini et al. 2002; Jacob et al. 1998].
Men with genitourinary malignancies make up a unique subset of patients with cancer since their treatment has a direct and structural impact on the male reproductive tract. Although few men undergoing prostate cancer treatment cite fertility as a concern, the prevalence of prostate cancer in young men is growing [Boyd et al. 2006]. In a large review of over 14,000 men undergoing radical prostatectomy, 476 were 45 years of age or younger at the time of surgery [Magheli et al. 2007]. For these men and their families, fertility needs may not yet have been met. If sperm are not cryopreserved preoperatively, testicular and/or epididymal sperm extraction in conjunction with in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) offer the only chances to father offspring. Regarding radiotherapy for prostate cancer, external beam therapy seems to have a greater negative impact on spermatogenesis than does brachytherapy [Mydlo and Lebed, 2004; Daniell and Tam, 1998]. In a similar manner to those with prostate cancer, the fertility potential for most men with bladder cancer is not a significant concern due to age at diagnosis; however, young men may also develop urothelial carcinoma and elect to undergo various therapies. Smaller studies of men undergoing intravesical chemotherapy showed greater changes in semen parameters in men treated with Bacillus Calmette-Guerin (BCG) as opposed to mitomycin C [Raviv et al. 2005]. A study of prostate-sparing cystectomy reported sperm in postejaculate urine samples [Colombo et al. 2001].
Fertility following treatment of thyroid cancer with radioactive iodine is excellent; however, the treatment of pediatric sarcomas and rectal cancers results in a high rate of testicular dysfunction [Mansky et al. 2007; Longhi et al. 2003; Hyer et al. 2002].
Two main concerns have been raised regarding risk of cancer in the children of cancer patients: does having cancer increase the risk of passing on this risk to one’s offspring; and do cancer therapies portend any mutagenic risk? In particular, in the era of assisted reproductive techniques (ART) such as IVF/ICSI, is there any greater risk than in the past?
Prior to IVF/ICSI, studies did not demonstrate any increased risk of malignancy in the offspring of cancer survivors except in cases of known heritable diseases [Winther et al. 2004; Sankila et al. 1998; Hawkins et al. 1989]. However, immediately following chemotherapy, there is a risk of sperm chromosomal abnormalities and aneuploidy which seems to lessen over time [Wyrobek et al. 2005; Thomas et al. 2004; Frias et al. 2003; De Mas et al. 2001; Robbins et al. 1997]. Chromosome analyses of testicular cancer patients after chemotherapy demonstrated no significant difference in the frequency of chromosomal abnormalities before and after therapy [Martin, 1998].
Semen for sperm cryopreservation is generally obtained by masturbation. For many men, this may be an embarrassing or uncomfortable process. It is critical that men understand how to collect semen and that they be offered a private and relaxing environment to do so. Alternatively, men may collect a semen sample at home or another location than the clinic, providing that they keep the specimen at body temperature and return it to the lab within approximately 45 minutes to 1 hour after collection. Lubricants should be avoided as they can contaminate the specimens. The entire specimen should be collected, particularly in light of the fact that more sperm are present at the beginning of the ejaculate than at the end [WHO, 1999]. Wide-mouth specimen containers should be tested by each laboratory to ensure that they are compatible with semen collection and are not harmful to sperm.
Some men have difficulty providing semen specimens with masturbation. An alternative is to collect the sample with a condom. However, the condom must be approved by the laboratory as commercially available condoms generally contain spermicides that will kill sperm. This method typically results in fewer sperm being collected but may be necessary for some men. In addition, anxiety, religious beliefs, pain, medications, and other factors may make semen collection challenging.
The adolescent male population is one in which extremely careful counseling and tactful, age-appropriate instructions are necessary, as these patients are at risk for emotional distress from this process. Parents should be included in discussions, although separate sessions with the adolescent are often useful. Unfortunately, no guidelines exist for the best approach to semen cryopreservation in the adolescent male, but individual institutional strategies are available [Leonard et al. 2004].
At the time of diagnosis, many cancer patients are inpatients, and it may be at this time that many are first offered sperm cryopreservation. The logistics of collecting a specimen in this setting can be challenging, given the disruptions and interruptions that can occur in an inpatient room or bathroom. In addition, some men are quite ill and debilitated by their cancer at the time of presentation and are unable to produce a sample. In these cases, surgical sperm retrieval can be offered.
Semen analyses are performed on all samples prior to cryopreservation. Semen parameters should be documented in accordance with the WHO guidelines [WHO, 1999]. Sometimes multiple collections are recommended depending on the number of motile sperm seen, the time since the last ejaculation, and individual variability.
The freezing of spermatozoa was first described as early as the 18th century, but modern techniques made cryopreservation practical and feasible in the mid 1900s with the development of sperm cryoprotectants. Today, common uses of sperm cryopreservation include banking sperm prior to vasectomy, at the time of vasectomy reversal for backup, prior to men engaging in potentially life-threatening activities (e.g. military deployment), and—pertinent to this review—prior to gonadotoxic, life-saving cancer treatments.
When semen is cryopreserved, a small aliquot is frozen separately, thawed, and reanalyzed after the initial freeze. This ‘test thaw’ allows the postthaw survival to be determined as it can vary among individuals and even among different ejaculates from the same person [Leonard et al. 2004]. Postthaw sperm motility is a good representation of the entire ejaculate and gives a reliable estimate of the total motile sperm count for that sample in the future [Padron et al. 1997].
While paternity with cryopreserved sperm clearly is possible, the freeze–thaw process may either negatively affect sperm quality and/or enhance any underlying sperm defects [Gandini et al. 2006a; Bolten et al. 2005]. Currently, sperm are kept in vials with cryoprotective agents such as glycerol in combination with test yolk buffer, and these vials can be stored indefinitely in liquid nitrogen. Future techniques of dry storage may afford less damage to sperm [Meyers, 2006].
The number of specimens that should be cryopreserved will differ for each patient. Determining factors include age, number of previous children, and semen quality. Abstinence of at least 48 hours will typically maximize the yield of sperm per sample [WHO, 1999]. Even with time constraints and pressing health issues, men should be encouraged to consider sperm banking. Particularly in the era of ART, it is now possible to cryopreserve samples with low sperm counts that in the past were considered inadequate for freezing [Sanger et al. 1992]. Poor semen quality has not been shown to affect fertilization or pregnancy rates after cryopreservation and IVF/ICSI, as long as live sperm can be recovered [Kuczynski et al. 2001].
It has been the practice of the author to encourage patients to initiate and complete sperm cryopreservation before starting any cancer therapy that affects the reproductive system. For example, in the setting of radical orchiectomy for testicular cancer, it is easier for a patient to ejaculate without a fresh inguinal incision; also, if that patient is found to have azoospermia, arrangements can be made to perform surgical sperm retrieval under the same anesthetic. If chemotherapy or radiation treatment has already been initiated, cryopreservation of semen is still possible during treatment, at least until the patient becomes azoospermic [Carson et al. 1991]. It should be noted that the effects of these gonadotoxic agents on sperm are largely unknown. Animal studies demonstrate a high incidence of mutagenic effects in offspring from matings that take place during immediately following treatment of the male with chemotherapy or radiation [Meistrich, 1993]. Increased frequency of sperm aneuploidy has also been reported after the initiation of chemotherapy and may persist up to 18 months or longer [De Mas et al. 2001]. While the clinical impact of such effects in humans is unknown, sperm cryopreservation should ideally be performed before initiation of chemotherapy or radiotherapy. Otherwise, men are advised to wait 12–18 months after the completion of therapy before pursuing fertility treatments [Shin et al. 2005].
Over half of cancer patients desire future fertility, including over three quarters of those without children at the time of their cancer diagnosis [Saito et al. 2005; Schover et al. 2002a]. Currently, sperm banking is the only pretreatment strategy for male cancer patients to preserve their future fertility [Dohle et al. 2005]. However, less than a quarter of cancer patients bank sperm, and the most common reason for not doing so is lack of information [Schover et al. 2002a]. Only two thirds of men awaiting cancer therapy are aware of sperm banking [Edge et al. 2006]. Schover et al. also showed that over 90% of responding oncologists felt that sperm banking should be offered to all men before treatment, but almost half failed to do so [Schover et al. 2002b]. Reasons for this included time, high costs, and lack of convenient facilities. Only 10% claimed that they offered sperm banking to all eligible men despite evidence suggesting at least 50% of young men with cancer are interested in doing so [Magelssen et al. 2005].
Reebals et al. addressed oncology nurse practice issues in determining whether newly diagnosed adolescent male patients are offered the option of sperm banking before undergoing chemotherapy treatment. They distributed questionnaires to nurses and nurse practitioners who care for adolescent male cancer patients at the time of diagnosis, during chemotherapy, and during follow-up care. Over 95% of respondents agreed that all male patients undergoing cancer treatment should be offered sperm banking. Oncologists and nurse practitioners were seen as appropriate professionals to discuss this option. The authors concluded that lack of knowledge regarding sperm banking limited nurses’ willingness to discuss this topic, and education regarding cryopreservation could improve knowledge and practice patterns [Reebals et al. 2006].
Saito et al. reported a positive psychological effect in 80% of interviewed cancer patients who banked sperm. They found that, in particular, if sperm was banked on the patient’s own initiative, that doing so offered encouragement during therapy [Saito et al. 2005].
There are a variety of reasons why a patient may choose not to cryopreserve semen prior to starting cancer treatments, including modesty of both the patient and healthcare provider, privacy, discomfort, cost, urgency to begin treatment, and access to sperm banking facilities. Schover et al. found that the most common reason patients did not bank sperm was because of the lack of information [Schover et al. 2002a].
In 1995, Koeppel reported over 50,000 new cases of cancer in men under the age of 35 and realized that with rising survival rates and the harmful effects of treatment on fertility potential that semen cryopreservation should be offered to these patients [Koeppel, 1995]. The author acknowledged the controversies regarding the practicality and usage of sperm banking including the challenges faced by healthcare professionals in discussing such sensitive issues with patients. Oncology nurses were identified as key members of the treatment teams who could discuss infertility and sperm banking with patients at the most opportune time, before initiation of chemotherapy. It was recognized that improved knowledge would reinforce the importance of offering sperm banking to circumvent treatment-induced infertility.
Finding a sperm bank for a patient should not be a barrier in discussing the option. Information about sperm banks is readily available online. Most banks will have mail kits available that allow patients to collect sample at home and ship them to the sperm bank. This approach allows for privacy and convenience for the patient.
Cost has been identified as an obstacle for patients. Schover et al. demonstrated that both physicians and patients are under the impression that sperm cryopreservation is too costly [Schover et al. 2002b]. Although cost varies by facility, it is estimated that initial processing fees are approximately US$350 with monthly storage fees ranging from US$10 to US$50 per month. Insurance coverage is variable, but some will cover a portion of the cost, particularly in the setting of cancer treatment. National agencies such as the American Cancer Society may also have financial aid programs. Many sperm banks also offer payment plans based on need and income.
Canada and Schover acknowledged the limited time oncologists have with each patient, and the they suggested that training oncology nurses, social workers, and nurse practitioners to discuss infertility with new cancer patients is a reasonable approach to this barrier [Canada and Schover, 2005]. Educational materials including patient education sheets and interactive computer programs for patients and their families are useful. Educating healthcare providers via lectures, grand rounds, and in-service presentations is encouraged.
Developing an efficient, seamless system to provide this service to cancer patients during such an emotional time is also critical. Phone numbers and protocols should be readily available on inpatient wards and in outpatient clinics. Semen collection rooms should be readily accessible to patients.
Although semen collection is recommended prior to starting treatment, the urgency to start therapy sometimes trumps the ability to provide a sample for cryopreservation. In these cases, collection is possible after starting therapy, however the impact of chemotherapeutic and radiotherapy regimens on the risk of genetic defects in the offspring remains unknown. Patients and their families must be counseled as such. Some authors report that samples collected within 10–14 days of starting treatment may still be safe to use for future ART, based on sperm transit times through the reproductive tract [Chatterjee et al. 2000].
Lastly, there may be legal considerations surrounding sperm banking that need to be addressed. As summarized by Leonard et al. the law surrounding cryopreservation of semen is still uncertain [Leonard et al. 2004]. It remains unclear whether semen is categorized as property, person, or a unique material that is neither person nor property. In addition, the disposition of cryopreserved specimens in the event of a dispute remains unclear [Schuster et al. 2003]. Consent forms and contracts are important supporting documents for sperm banking, and they should address to whom the sperm belongs, what will happen in the event of death, and how payments for these services will be handled. Confounding factors may include cases of minors or in instances where there is potential for secondary gains (e.g. inheritance).
While adult male cancer patients may be more willing to accept the notion of sperm banking to preserve future fertility, adolescents may be intimidated and embarrassed by the concept. Their fertility wishes may not be realized for many years, and the long-term psychosocial impact of infertility on survivors of childhood cancer remain largely unknown [Zebrack and Zeltzer, 2003]. In addition, opinions vary regarding the most appropriate age for discussing sperm banking and who should be responsible for addressing this issue.
The exact age at which sperm production first begins is unknown and probably varies based on individual factors. Enlargement of the testes represents a transition from Tanner stage I to II, and it is around and after this time that spermatogenesis likely begins, even prior to the adolescent growth spurt [Nielsen et al. 1986; Hirsch et al. 1985]. Nevertheless, adolescent males with cancer, ranging from age 14 to 17 years, have been found to be good candidates for sperm banking [Bahadur et al. 2002a; Kliesch et al. 1996].
Ginsberg et al. examined the feasibility of offering sperm banking to young male cancer patients and determined the beliefs and decision-making processes of these patients and their parents. Of the 68 patients in their study who collected semen samples, 50 of them completed the study. They found that 80% of the patients made the decision to bank sperm with their parents, and that all of the patients who banked sperm felt that they were making the right decision to do so. Patients and parents alike wanted information about semen cryopreservation. The authors concluded that because semen quality was dramatically reduced, even by one course of gonadotoxic therapy, that sperm banking should be offered to all eligible patients prior to therapy. Parents played an important role in the decision to bank sperm [Ginsberg et al. 2008].
Klosky et al. assessed sperm cryopreservation among males newly diagnosed with cancer aged 13 years and older. Oncologists assigned infertility risk to patients and reported whether their patients engaged in sperm cryopreservation. Less than 30% of their patients banked sperm. The authors found that the decision to cryopreserve semen was associated with a number of factors including a diagnosis of central nervous system malignancy or noncentral nervous system solid tumor diagnosis, higher socioeconomic status, and not being a member of an Evangelical religious group. They concluded that sperm banking was underutilized by adolescent males and that newer strategies were needed to increase the number of these patients who participated this fertility-preserving activity [Klosky et al. 2009].
Emotional maturity is another important concept when discussing sperm banking in adolescent males. Boys who are not physically mature may still be able to collect sperm. Conversely, a physically mature adolescent may not be emotionally or sexually mature to perform a semen collection by masturbation.
A low—but still clinically significant—percentage of men with cancer who present for sperm banking will be azoospermic or will be unable to collect a semen sample. In such cases, surgical sperm retrieval techniques may be offered. Oftentimes, these procedures require a concerted and coordinated effort between the urologist and the fertility laboratory. Time pressures are typically present as these patients generally need to begin urgent therapy. The various approaches are discussed below, and they may be able to be scheduled concomitantly with any oncologically related procedures such as vascular access, lymph node sampling, or bone marrow biopsies.
Testicular sperm extraction (TESE) refers to an incisional testicular biopsy performed to obtain sperm for cryopreservation. Sperm obtained with this approach may only be used for ART [Vanderzwalmen et al. 1997]. For these men, it is difficult to predict success rates for sperm retrieval, although roughly half of azoospermic men with testicular cancer or malignant lymphomas will have sperm found on TESE [Schrader et al. 2003; Kim et al. 1997]. In addition, men with testicular cancer undergoing radical orchiectomy may have microdissection TESE performed on the removed testicle [Binsaleh et al. 2004; Baniel and Sella, 2001]. These men may also be scheduled for a simultaneous sperm retrieval procedure under anesthesia on the contralateral testicle.
For male cancer survivors who are azoospermic and who did not cryopreserve sperm prior to their cancer therapy, testicular sperm retrieval techniques in conjunction with ART can be offered [Tournaye et al. 1996; Devroey et al. 1995]. Microdissection TESE affords retrieval rates of approximately 50% in men with postchemotherapy azoospermia [Meseguer et al. 2003; Damani et al. 2002; Chan et al. 2001].
Microsurgical epididymal sperm aspiration is a procedure used to obtain sperm from the epididymides in the setting of obstructive azoospermia. An example where this approach would be indicated in a cancer patient with azoospermia is following a radical prostatectomy which from a reproductive perspective is similar to postvasectomy patient. In this patient population, testicular function is usually preserved, and cryopreserved sperm have been shown to be suitable for ART [Janzen et al. 2000; Oates et al. 1996].
Some patients with cancer have undergone surgical procedures that affect their ejaculatory function. Retroperotineal lymph node dissections for testicular cancer and low-anterior and abdominoperineal resections for gastrointestinal malignancies can put men at risk for ejaculatory failure, despite improvements in surgical techniques. When medical treatment fails to improve emission and ejaculation, then electroejaculation (EEJ) may be offered. EEJ has been shown to be an effective way to retrieve sperm for ART [Ohl et al. 2001, 1991]. Sperm quality tends to be impaired in these patients, and pregnancy rates are better when these sperm are used for IVF/ICSI rather than intrauterine insemination (IUI) [Ohl et al. 2001; Schatte et al. 2000; Chung et al. 1997]. EEJ should be used with caution in the setting of thrombocytopenia or leukopenia given the potential risks of bleeding or infection.
While it is generally accepted that cancer and cancer therapies adversely affect a man’s reproductive potential, the outcomes of ART up until recently has only been addressed in case reports and small studies. This is due, in part, to the advances in ICSI which has revolutionized the treatment of male infertility due to the need for only a few sperm either in the ejaculate or testicular tissue. Cryopreserved sperm may be used for IUI and/or IVF with ICSI. How to best use frozen sperm for ART depends on the quantity and quality of the sperm, how well the sperm survive the freeze–thaw process, the presence of any female factors, and patient/couple preference.
Sanger et al. reviewed the literature from an era prior to widespread use of ICSI. Fifty four deliveries resulting from cryopreserved semen of male cancer survivors from fertility clinics and another 61 deliveries resulting from the use of cryopreserved semen from male cancer survivors were reported from sperm banks [Sanger et al. 1992].
Naysmith et al. assessed the effect of cancer treatments on the natural and assisted reproductive potentials of men. Semen samples were analyzed before and after cancer therapy. Twenty seven per cent of the men had abnormal semen parameters before treatment. Following treatment, 68% of the samples were abnormal. Twenty three per cent of men developed azoospermia after treatment. Pretreatment sperm cryopreservation improved the fertility potential of 55% of their patients. The authors commented that improving awareness and education of patients and providers on the impact of cancer and cancer treatments on fertility is essential. They also stressed that with the advent of ICSI, all men with cancer should be offered pretreatment sperm cryopreservation as even men with very low sperm concentrations the chance of conception is very reasonable [Naysmith et al. 1998].
Schmidt et al. reported their experience with couples referred for ART because of male-factor infertility due to cancer and cancer treatment. Most of their patients had testicular cancer and lymphomas. Ninety per cent of the men had adjuvant treatment with chemotherapy and/or radiation therapy. Perhaps most impressively, semen was cryopreserved in 82% of their men prior to treatment. Following cancer therapy, 43% of the men had motile spermatozoa in the ejaculate, while 57% were azoospermic. Both fresh and cryopreserved sperm were used, and the clinical pregnancy rates per cycle were 14.8% after IUI, 38.6% after ICSI, and 25% after ICSI–frozen embryo transfer with corresponding delivery rates of 11.1%, 30.5%, and 21%. Cryopreserved semen was used in 58% of the pregnancies. Of note, the delivery rate per cycle was similar after use of fresh or cryopreserved sperm. The authors concluded that male cancer survivors have a good chance of fathering a child by using either fresh ejaculated sperm or cryopreserved sperm and that ICSI be used as a first choice, given the better success rates with ICSI as well as the need for overall higher total motile sperm counts for IUI which are not always available postthaw [Schmidt et al. 2004].
These reports of successful pregnancies with cryopreserved sperm in male cancer survivors are supported by numerous other studies [Meseguer et al. 2006; Zorn et al. 2006; Agarwal et al. 2004; Ginsburg et al. 2001; Lass et al. 1998; Rosenlund et al. 1998; Khalifa et al. 1992; Palermo et al. 1992].
van Casteren et al. reported their experience with ART using cryopreserved semen of cancer patients. Five hundred and fifty seven male cancer patients banked 749 semen samples. Out of the total group of 557 men who cryopreserved semen, 218 (39%) returned for semen analysis after cancer treatment. Motile sperm were found in 155 (71.1%) of these 218 men. Twenty of these 218 men reported a spontaneous pregnancy. While only 42 of the cancer survivors (9.6%) ultimately requested the use of their banked semen, these men would have been unable to father their own biologically-related children if their sperm had not been banked prior to therapy. Half of these men were successful in having live births using IVF/ICSI [van Casteren et al. 2008].
Conceptually, there could be differences in ICSI success rates when using fresh versus cryopreserved sperm, although current studies indicate no difference in pregnancy outcomes between the two [Borges et al. 2007; Wald et al. 2006; Ulug et al. 2005].
A few studies have looked at the utilization of cryopreserved sperm by male cancer survivors. In one study of 258 men, only 18 returned for treatment [Audrins et al. 1999]. Ginsburg et al. found that at their fertility center, 19 male cancer survivors underwent a total of 35 IVF cycles, and 11 of these cycles used cryopreserved semen [Ginsburg et al. 2001]. In a larger study, Magelssen et al. looked at posttreatment paternity in 1388 testicular cancer survivors: 422 of these men had cryopreserved semen after orchiectomy. Overall, only 29 men (7%) used their cryopreserved semen for ART, while 67 men (17%) fathered at least one child with fresh semen [Magelssen et al. 2005, 2006].
Lastly, according to a study by Saito et al. if male cancer survivors had return of spermatogenesis following treatment, none would choose to use their cryopreserved sperm. Even if the cryopreserved sperm was not used, as in most cases, a positive psychological effect of having banked sperm was achieved [Saito et al. 2005].
An exciting new direction for fertility preservation in men with cancer is implementing stem cell technologies for germ cell transplantation and testicular grafting. Spermatogonial stem cells may be used in the future for preservation of testicular tissue and fertility preservation in men and boys prior to treatment, as these cells are capable of self-renewal, proliferation, and repopulation of the seminiferous tubules [Shin et al. 2005].
Schlatt et al.  recently reviewed the physiology of spermatogonial stem cells in rodent and primate testes and concluded that while germ cell transplantation has become an important research tool in rodents and other animal models [Dobrinski, 2005a, 2005b; Honaramooz et al. 2003; Zhang et al. 2003; Izadyar et al. 2002; Nagano et al. 2002; Avarbock et al. 1996; Brinster and Avarbock, 1994], the clinical application in humans remains experimental. Regarding testicular grafting as another exciting strategy for fertility preservation in males prior to gonadotoxic therapy, both autologous and xenologous transfer of immature tissue revealed a high regenerative potential of immature testicular tissue and generation of sperm in rodents and primates. Similarly to germ cell transplantation, however, further research is needed before an application in humans can be considered safe and efficient.
Despite current limitations in regard to generation of sperm from cryopreserved male germline cells and tissues, and since future improvements of germ cell transplantation and grafting approaches are likely, retrieval and cryopreservation of testicular tissue prior to therapy should be offered to young men with cancer who are at high risk of fertility loss, as this could be their only option to maintain their fertility potential after treatment [Goossens and Tournaye, 2006; Jahnukainen et al. 2006]. In addition, prepubertal testicular tissue from boys facing gonadotoxic treatment may be cryopreserved under special conditions. Doing so may offer fertility preservation for these young patients in the future [Keros et al. 2007].
A potential concern about using spermatogonial stem cells and testicular grafts is the theoretical risk of restoring cancer cells back into the recipient. This effect has been demonstrated in leukemic rat models [Jahnukainen et al. 2001]. However, efforts have been made to reduce this risk using telomerase in culture [Feng et al. 2002]. The use of embryonic stem cell technology to treat infertile men is also under investigation, although significantly more translational research is needed, before these technologies are applied to the treatment of human male infertility [Toyooka et al. 2003].
Improvements in cancer treatments have resulted in more men living into their reproductive years, and fertility is an important measure of quality of life in this patient population. However, all cancer therapies—chemotherapy, radiotherapy, and surgery—are potential threats to a man’s reproductive potential. The type of treatment(s) and individual susceptibilities to the deleterious effects of these treatments make it next to impossible to predict whether or not a man will recover spermatogenesis after therapy and what his sperms’ potential is to safely fertilize an egg. Stem cell transplantation technologies may hold promise in the future but are unavailable for use in humans at this time. Advances in ART now provide more men opportunities become biological fathers, even in the setting of poor semen parameters. Thus, sperm cryopreservation prior to initiating life-saving cancer treatment offers men and their families hope and the best chances to father biologically related children in the future. It is a safe and effective means of preserving a man’s fertility and should be offered to all men with cancer before treatment. Posttreatment male infertility also may be treated with ART and advances in surgical sperm retrieval. Barriers to sperm banking still exist, but the sensitive nature of many of these can be overcome by patient and provider education, as well as deliberate, coordinated strategies at comprehensive cancer care centers to make fertility preservation for male cancer patients a priority during pretreatment planning.
The authors declare that there is no conflict of interest.