Oncofertility and the Male Cancer Patient
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- Trost, L.W. & Brannigan, R.E. Curr. Treat. Options in Oncol. (2012) 13: 146. doi:10.1007/s11864-012-0191-7
Oncofertility as a discipline plays an important, adjunctive role in the treatment of male patients with cancer. Despite recommendations by the American Society of Clinical Oncology, many clinicians managing malignancies in males fail to consistently incorporate fertility preservation as a routine aspect of health care. Providers involved in the treatment of oncologic patients should have an awareness of the impact of their prescribed treatments on reproductive potential, just as they would be knowledgeable of the potential deleterious effects of cancer therapies on vital organs such as the kidneys, lungs, and liver. Providers should then have a discussion with their patients regarding these potential adverse therapeutic effects or consult a fertility preservation specialist to discuss these matters and fertility preservation options with the patient. Cryopreservation of sperm remains an excellent option for male fertility preservation as it is readily available and results in storage of viable gametes for future use in the event of post treatment infertility. With the use of assisted reproductive techniques (ART), cryopreserved sperm may ultimately result in successful paternity, even in the setting of very low numbers of stored sperm. While sperm cryopreservation is usually an option for adolescent and adult males, fertility preservation in pre-pubertal males presents a more challenging problem. To date, no clinically proven methods are available to preserve fertility in these males. However, some centers do offer experimental protocols under the oversight of an IRB, such as testicular tissue cryopreservation in these males. The hope is that one day science will provide a mechanism for immature germ cells from the testicular tissue of these patients to be used in vivo or in vitro to facilitate reproduction. In closing, studies have shown that the patient’s regard for his provider is enhanced when the issue fertility preservation is raised. While oncologic care is often fraught with time constraints and acute medical concerns, fertility preservation care in the male can typically be administered quickly and without disruption of the overall plan of care.
KeywordsOncofertilityMale patientsCancerAssisted reproductive techniquesCryopreservation
Assisted reproductive techniques
American Society of Clinical Oncology
American Society for Reproductive Medicine
Follicle stimulating hormone
Gonadotropic releasing hormone
Human chorionic gonadotropin
Intracytoplasmic sperm injection
Retroperitoneal lymph node dissection
Oncofertility is a relatively new field, with an underlying purpose of preserving reproductive function in patients with malignancy without compromising overall care. Due in part, to advancing medical, surgical, and radiologic treatments available, cancer patients are experiencing improved outcomes and longevity. Current epidemiologic estimates based on SEER data report that 9% of patients diagnosed with cancer from 2004 to 2008 were younger than 45 years old, with 1% under age 20 . Stated otherwise, “childhood” malignancy is estimated to affect up to 1/168 Americans aged 15–30 . Additionally, the prevalence of young cancer survivors is significant, as the majority of cancer patients less than age 50 experience 5-year survival rates of 75–80% [1, 3, 4, 5•, 6].
Given the improved survival and longevity of young cancer patients, an increased focus has been placed on optimizing survivorship issues such as fertility, without negatively impacting therapeutic outcomes. Beginning in 2005, both the American Society for Reproductive Medicine (ASRM) and the American Society of Clinical Oncology (ASCO) addressed the issue of infertility after cancer with recommendations for providers treating both adult and pediatric malignancy [7, 8]. Among the recommendations, physicians were encouraged to discuss the possible impact of cancer and cancer therapies on fertility, make early referrals of interested patients to reproductive specialists, and address fertility preserving options such as sperm cryopreservation when appropriate.
The underlying etiology of cancer-related infertility is often multifactorial in nature, including the impact of the malignancy and the effects of surgical treatment, radiation therapy, and chemotherapy which all potentially disrupt normal male fertility potential. As an estimated 30% of therapies directed towards childhood malignancies have an impact on fertility, the prevalence of iatrogenic infertility among adult survivors of pediatric cancer is significant . The goal of the current article is to review the physiology of spermatogenesis, provide an up to date literature review on the impact of cancer treatment on male fertility, and discuss available fertility preservation options.
To better comprehend the effects of cancer treatment on male-factor fertility, an understanding of embryogenesis and the physiology of spermatogenesis is important. Although the testis is fully developed at birth, with an estimated 83,000,000 diploid germ cells present by age 10, true spermatogenesis (transformation of germ-line cells into mature spermatozoa) does not occur until the time of puberty . The existing germ cell lines are subdivided into A (dark), A (pale), and B spermatogonia [11–13, 14•]. While A (dark) stem cells are predominantly mitotically quiescent, A (pale) cells act as the functional progenitor cells, undergoing a lifelong process of recurrent spermatogenesis and self renewal with each cycle [15–17]. Given the slow rate of cell turnover of A (dark) cells, they serve as a diploid reserve pool, being activated predominantly at puberty and following episodes of toxic injury with stem cell depletion to facilitate restoration of the A (dark) cell population [18–23]. Additionally, as A (dark) cells are mitotically inactive, they are more resilient to chemical and radiologic insults than the more active A (pale) cells, and they function as a “restorative cell” in cases of severe injury to spermatogenesis [21–23]. Thus, both A (dark) cells and A (pale) cells permit a degree of reproductive resilience in the setting of sustained germ cell damage [23, 24].
Etiology of infertility
Risk of impaired fertility potential with commonly utilized chemotherapeutic and radiation therapy regimens
BMT / SCT
Alkylating agent + radiation
Testicular, hematopoietic malignancies, neuroblastoma, BMT / SCT
Hematopoietic malignancies, sarcoma, neuroblastoma
MOPP / COPP
BMT / SCT
>2.5 Gy (adult)
Testicular / hematopoietic malignancies
>6 Gy (child)
Testicular / hematopoietic malignancies, sarcoma
Testicular malignancy, effects of scatter
Given the complex interaction of the host immune response and the effects of the primary malignancy directly, there are several factors which may lead to decreased overall fertility. Carcinogenesis may result in a systemic inflammatory state. The secretion of metabolically active cytokines can lead to direct damage to the germinal epithelium. Elevated systemic temperatures, part of the immune response to some malignancies, can lead to massive germ cell loss via germ cell sloughing. Finally, cancer can itself become a chronic disease state associated with malnourishment, which can negatively impact reproductive potential [25•].
In addition to direct effects of the malignant process on germ cells, fertility may be impacted indirectly through alterations in systemic hormones. Testicular malignancies in particular may be hormonally active with production of hCG which secondarily feeds back to the hypothalamus and pituitary to decrease release of GnRH and LH, thus resulting in diminished spermatogenesis. Hematopoietic malignancies may result in either direct infiltration of the central nervous system, including the hypothalamus and pituitary, or may dysregulate systemic processes including thyroid and adrenal hormones . Additionally, the stress response associated with malignancy and metabolic derangements may further upset the hormonal balance and decrease optimal fertility.
Several authors have reported on the effect of primary malignancy on baseline fertility status prior to undergoing any form of therapeutic treatment. Although numerous malignancies are associated with impaired semen parameters, leukemias, lymphomas and testicular carcinomas are the most frequently identified, with germ cell tumors demonstrating the highest overall risk of abnormal spermatogenesis [27, 28].
Rueffer and colleagues reported a 70% reduction in semen quality in males diagnosed with Hodgkin’s disease . Similarly, Schover and colleagues reviewed 764 men who presented for sperm banking prior to treatment of various malignancies and found that 64% exhibited abnormalities in the semen analysis, with 12% identified as azoospermic or severely oligospermic with non-motile spermatozoa . Other reports have identified spermatic chromosomal aneuploidies in patients with malignancy, with improvements noted following definitive treatment of the malignancy, further highlighting the contributing role of malignancy as a source of infertility [31–33].
Although not applicable to all malignancies, surgery is one potential iatrogenic cause of infertility, depending on the location and extent of surgery performed. Major pelvic surgeries involving the GU and GI tracts such as prostatectomy, cystectomy, pelvic exenteration, low colonic resection, and retroperitoneal lymph node dissection (RPLND), among others, may result in injury to the sympathetic, parasympathetic, or pelvic nerves in addition to direct injury or resection of the ejaculatory structures (vas deferens, seminal vesicles, ). Surgery may also indirectly preclude fertility through decreasing erectile or ejaculatory function, in some cases necessitating sperm retrieval and assisted reproductive techniques (ART). In an attempt to reduce the impact on fertility, technical modifications have been made to operative procedures such as the addition of the nerve-sparing portion to radical prostatectomy and RPLND, with resultant improved preservation of erectile function through the former and ejaculatory function through the latter. To highlight the impact of a nerve-sparing approach in men undergoing the RPLND procedure for testicular cancer, Foster and colleagues reported a 95–98% preserved antegrade ejaculation rate and a 76% paternity rate .
Orchiectomy, performed for germ-cell tumors, results in the loss of gonadal tissue and thus decreased sperm production. Peterson and colleagues reported a reduction in sperm concentration in 30/35 men undergoing unilateral orchiectomy, with 3/35 developing new onset azoospermia . Similarly, Liquori and colleagues reported significant reductions in sperm concentration following unilateral orchiectomy with poorer outcomes noted in patients with a non-seminomatous compared to seminomatous germ cell tumors . Despite these results, Herr and colleagues demonstrated that fertility remains a possibility following orchiectomy with a reported paternity rate of 65% (41/63) among men having undergone unilateral orchiectomy for stage I testicular cancer .
Mechanism for impaired fertility with chemotherapy and radiation therapy
In addition to the effects of factors related to the primary malignancy and surgical treatment performed, various regimens of chemotherapy and radiation therapy have a variable impact on fertility. As previously described, the seminiferous tubules contain germ cells as well as the support cells necessary for fertility including Sertoli cells, A (dark) and A (pale) spermatogonial cells, and Leydig cells. While Leydig cells are resilient to relatively high doses of chemoradiation with low risk of developing hypogonadism, A (pale) spermatogonia may undergo apoptosis at lower doses, thus requiring repopulation from A (dark) progenitor cells to restore fertility potential [37–39]. At higher doses of chemotherapy and/or radiation therapy, the A (dark) cells may also be significantly damaged, resulting in permanent azoospermia and destruction of the seminiferous epithelium, with a Sertoli-Cell-Only pattern remaining [39, 40]. In addition to the dosage applied, other aspects of therapy which may impact fertility include the specific chemotherapeutic agent administered, site-specific and total dose of radiation, and the fractionation / delivery schedule . As the effects of chemotherapy and radiation therapy are independent of the patient’s pubertal status, children treated at a young age are also at risk of developing persistent, life-long impairments in fertility [41, 42]. More specifically, recent studies show that prepubertal status does not confer protection of reproductive potential in males being treated for cancer. Given that the treatment for malignancy varies by tumor type and stage, the individual effects of radiation therapy and chemotherapy will be reviewed individually in addition to their effects as combined modalities.
Radiation damage to the testicle occurs either through direct exposure or through the effects of scatter, such as occurs with radiation delivered to the retroperitoneum. Radiation therapy results in DNA damage to all testicular cell types including germ cells, Sertoli cells, and Leydig cells, each with variable levels of sensitivity. This is potentially significant when considering ART, as radiation may result in DNA fragmentation within existing sperm.
In addition to the total dose received, the fractionation or delivery schedule also impacts the degree of damage sustained. A higher dose of radiation delivered over fewer fractions has been shown to result in less damage compared to lower doses administered over a more extended timeline, even when equivalent total doses are achieved [43, 44]. Although the exact mechanism for the increased injury with a prolonged, reduced dose schedule is not fully understood, one possibility is that repeated damage to the A (dark) and A (pale) cells results in inability to sufficiently regenerate the reserve germ cells between treatments. Several studies have examined various doses of radiation on the development of azoospermia, as well as the time required to renew spermatogenesis. As previously noted, the germ cells demonstrate significant sensitivity to radiation compared to other cell types in the testes, possibly secondary to their high mitotic rate. Doses of 0.1 Gray (Gy) have been shown to result in a temporary arrest of spermatogenesis, with a dose of 0.65 Gy resulting in azoospermia, and permanent azoospermia achieved in one study at levels as low as 1.2 Gy [45, 46]. This is particularly significant given that many protocols for testicular cancer implement dosages of 16–18 Gy, although treatment is typically delivered to the retroperitoneal lymph nodes, and not usually delivered directly to the testes.
The extent of damage sustained with spermatogenesis is also related in a temporal manner to the total dose received. Following radiation, sperm counts typically nadir at 6 months and recover according to the total dose received . Azoospermia is noted for a period of 9–18 months, 30 months, and 5 years following administration of <1 Gy, 2–3 Gy, and 4–6 Gy, respectively, while spermatozoa are again noted in the ejaculate at 6 months, 9–18 months, and 4 years with doses of 0.2 Gy, 1 Gy, and 10 Gy, respectively [43, 45, 48–50].
In contrast to the seminiferous tubules, Leydig cells are relatively radioresistant with doses of 20–30 Gy required to cause hypogonadism necessitating androgen replacement [51–53]. Levels <20 Gy may, however, result in subclinical hypogonadism, as LH elevations have been observed at reduced doses, indicating some degree of Leydig cell injury [37, 44, 54].
The effect of chemotherapy on overall fertility varies depending on the chemotherapeutic agent and dosage employed. Two classes of chemotherapeutic agents which have traditionally been more closely associated with infertility are alkylating agents (cyclophosphamide, chlorambucil, procarbazine, busulfan) and platinums (cisplatin, carboplatin), although antimetabolites, vinca alkaloids, and topoisomerase inhibitors have also been shown to be gonadotoxic [55–57].
As the majority of cancer treatment protocols call for multiagent therapies, it is difficult to isolate the effects of one agent on overall fertility. In general, the effects of chemotherapy are dose dependent and age independent. Similarly, the fractionation schedule of chemotherapy also impacts overall fertility, even in the setting of equivalent overall dosages administered. Patients receiving lower dose therapies over multiple fractions experience decreased fertility when compared to those receiving higher dosages delivered in fewer treatments . The effect of chemotherapy on sperm is likely prolonged, as chromosomal abnormalities have been detected up to 24 months following the last treatment, although these DNA changes may also be tied to the underlying malignancy and the body’s immune response to the neoplastic process .
Multiagent chemotherapy and combined chemotherapy and radiation therapy
The majority of studies on fertility outcomes following treatment for malignancy are in the setting of multiagent chemotherapy +/− radiation and are most commonly reported with hematopoietic and testicular malignancies. Hematopoietic malignancies, in particular, are frequently associated with impaired fertility potential and have seen significant transitions to newer chemotherapeutic regimens. The previously utilized protocol for Hodgkins lymphoma including mechlorethamine, oncovorin, procarbazine, and prednisone (MOPP) resulted in azoospermia in 85–90% of patients undergoing >3 courses of therapy with additional changes of increased LH, decreased testosterone, and development of gynecomastia. Treatment with cyclophosphamide-based therapy (COPP) similarly impacted fertility with one study showing 100% of patients being treated for Hodgkin’s disease sustaining azoospermia at follow-up ranging from 1 to 11 years post-therapy . A dose dependent effect is noted with cyclophosphamide-based regimens with total doses of 7.5–9 g/m2, >10 g/m2, and 19–20 g/m2 resulting in impairments in fertility, gonadal damage, and permanent sterility, respectively [42, 60–62]. At doses of 1 g/m2 and above, histologic analysis reveals spermatogonia present in <40% of seminiferous tubules. More recently, the treatment of Hodgkin’s lymphoma has evolved to include the use of Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). This has resulted in significant improvements in fertility potential with up to 90% of patients experiencing normal sperm counts 1 year following completion of therapy.
For patients undergoing bone marrow transplantation, recovery of spermatogenesis is dependent upon the initial conditioning therapy applied with 90% of patients who underwent treatment with cyclophosphamide alone recovering spermatogenesis . In contrast, among those conditioned with cyclophosphamide and total body radiation, only 17% went on to recover spermatogenesis, with recovery noted as late as 9 years post-treatment in one patient.
The treatment of testicular cancer is also associated with a potential risk of infertility. Lampe and colleagues reported on 178 patients treated with cisplatin-based chemotherapy for testicular cancer . Among 89 (of 178) patients with pre-treatment normospermia, 64%, 16%, and 20% were noted to have normospermia, oligospermia, and azoospermia (defined as <1 × 10^6 sperm/mL) following treatment. Recovery of spermatogenesis was noted to occur in 80% of men by 5 years post-treatment. When carboplatin is substituted for cisplatin, the impact on fertility is reduced. One study evaluating sperm recovery rates in pre-treatment normospermic patients following carboplatin based chemotherapy (BEC) for high risk stage I non-seminomatous germ cell tumors (NSGCT) demonstrated a return to normospermic status in 93% and 83% of patients receiving two versus four cycles of therapy, respectively .
Patients undergoing radiotherapy for seminomatous germ cell tumors are also at risk of infertility. Nalesnik and colleagues reported on 73 men treated with orchiectomy plus radiation therapy for stage 1-2a seminoma. Sixty-four percent (7/11) of the subgroup of patients who attempted to achieve pregnancy were successful, with 100% of the patients who supplied a semen analysis noted to have sperm present . Additional studies have examined the radiation protocol applied to assess for differences in outcomes including fertility status. In comparing a “dog-leg” (para-aortic lymph nodes and ipsilateral iliac nodes) to a para-aortic alone field of radiation, those who underwent the “dog-leg” protocol experienced statistically significant decreases in sperm counts compared to pre-radiation counts [66, 67]. Although the mechanism is not completely described, this may be due to an increased degree of scatter experienced to the remaining testicle given its closer proximity to the radiation field.
Although less frequently encountered in fertility practices due to an overall worse prognosis, primary CNS tumors are another class of malignancy which may be associated with secondary infertility. Patients undergoing cranial radiation with doses of 35–45 Gy have demonstrated a decreased production of gonadotrophins with subsequent impairment in spermatogenesis and also delayed puberty . However, these effects can often be successfully treated with gonadotropin hormonal supplementation, which typically will permit a return to normal reproductive function.
Male patients with a new diagnosis of malignancy who are at risk for infertility should undergo a discussion of fertility preservation options prior to initiation of cancer treatments. Cryopreservation of ejaculated semen samples is available at many centers and can typically be achieved rapidly, without impacting most oncologic treatment protocols. Although sperm cryopreservation remains the gold standard therapy for male fertility preservation, patients who have not undergone puberty and thus have not yet initiated spermatogenesis are not candidates for sperm banking. Pertinent clinical factors which may be used as a signal of potential onset of spermatogenesis include nocturnal seminal emission, testicular volumes >10–12 cm3, and Tanner Stage II development or greater.
For patients who have not yet achieved puberty, investigations are ongoing into alternative therapies including testicular tissue harvesting; however, given their experimental nature, these procedures should only be performed in the setting of an IRB-approved study protocol .
Sperm cryopreservation remains the best technique for fertility preservation in males undergoing potentially gonadotoxic therapies for malignancy. The process of sperm isolation is patient dependent, with the majority of patients able to provide sperm for cryopreservation via ejaculation without further methods required. As many patients with malignancy have pre-existing decreased sperm counts, a total of two to three samples should ideally be cryopreserved with a 48-hour period of abstinence prior to each ejaculation. Additionally, specimens should be obtained prior to chemotherapy or radiation therapy to minimize DNA damage within the cryopreserved sperm .
Methods of sperm procurement
Sperm Aspiration (PESA, TESA)
Can be used in setting of anaejaculation, retrograde ejaculation, and azoospermia.
Surgical Sperm Extraction (MESA, TESE, Micro-TESE)
Can be used in setting of anaejaculation, retrograde ejaculation, and azoospermia.
Sperm Retrieval from the Bladder
Can be used in the setting of retrograde ejaculation.
Can be used in the setting of anejaculation. This approach requires anesthesia when patients are neurologically intact.
This is the preferred method of sperm procurement. The approach requires an intact nervous system and active spermatogenesis.
Can be used in the setting of anejaculation or spinal cord injury. The approach requires an intact sacral arc nervous system.
In the absence of known familial or genetically-associated malignancy, male cancer patients undergoing systemic and localized treatments for malignancy have not been shown to have an increased rate of malignancy or genetic abnormalities in their offspring [73, 74]. Agarwal and colleagues prospectively reported on 29 males undergoing ART utilizing cryopreserved sperm obtained prior to treatment for malignancy . A total of 87 ART cycles were performed with 18.3% resulting in pregnancy, 75% (11/87) of which resulted in live births. None of the infants were noted to have congenital abnormalities. Similarly, one study reviewing fertility outcomes among 67 couples with male factor oncofertility undergoing ART found no differences in outcomes when comparing fresh versus cryopreserved sperm . The study otherwise reported 82% of men undergoing cryopreservation prior to cancer treatment with 57% subsequently developing azoospermia. A total of 151 ART cycles were performed with delivery rates of 11.1, 30.5, and 21% using IUI, ICSI, and ICSI-frozen embryo transfer (FER), respectively. Cryopreserved sperm were utilized in 58% of cases.
A retrospective, multicenter study out of China reviewed 1,548 males who underwent cryopreservation, with 1.9% (30/1548) undergoing collection for oncofertility purposes . The utilization rate over the 6 year period analyzed was low at 6.7% (2/30) with one live birth achieved via ICSI. Similarly, Van Casteren and colleagues reported on outcomes of 557 male patients who underwent sperm cryopreservation prior to oncologic therapy . Following cancer treatment, a total of 9.6% (42/557) of patients requested utilization of their cryopreserved sperm due to infertility, with successful live births noted in half of the men. Additional studies have similarly demonstrated the successful use of cryopreserved sperm in achieving paternity, with an overall utilization rates of 33–58% [76, 78–80].
Despite formal recommendations for discussion of fertility preservation prior to oncologic therapy, many barriers to routine implementation exist [7, 8]. Oncologists frequently cite concerns regarding a myriad of issues, including costs, poor patient prognosis, perceived inability of patients to provide semen samples, time constraints, lack of insurance coverage, inadequate facilities, and lack of awareness of available fertility preservation options [78–80, 81•]. Patients report discussing fertility preservation prior to oncologic therapy only 57–60% of the time, and they report being given the option for sperm banking in only 51–55% of cases [30, 82•]. These impairments to the delivery of care can frequently be overcome with the implementation of a formalized, institutional oncofertility program .
Importantly, beyond maintaining the possibility for future paternity, fertility preservation may also result in psychological benefits to the patient including a reduction in long-term distress and disappointment associated with loss of fertility [84, 85]. Fertility is also associated with self-identity and overall well being, with male patients suffering infertility reporting a perceived decrease in masculinity . Interestingly, 80% of cancer survivors report a positive self-outlook as to their potential as future parents. Although actual utilization rates of cryopreserved sperm over limited periods of follow-up are 10–15%, patients report the ability to bank sperm as providing them with a sense of security, reassurance regarding their future, and coping mechanisms for their underlying diagnosis [75, 87].
The clinical practice of fertility preservation frequently requires ethical considerations, particularly in the setting of advanced underlying malignancy. Commonly, patients have an expectation of maintained fertility and are not aware that the treatment of malignancy may lead to possible loss of future fertility. As such, a discussion of the patient’s wishes must take into account in the context of the underlying disease process and the patient’s prognosis. Additional factors which may be encountered include requests for post-mortem use of sperm, rights attributed to preserved material, and costs associated with ongoing semen cryopreservation, among others. The American Society for Reproductive Medicine has published a manuscript to help guide clinicians through the challenging ethical issues that can arise in the context of fertility preservation for patients who have been diagnosed with cancer .
With the overall improved treatment of malignancy that has emerged in the last several decades, the prevalence of male cancer survivors is increasing. In addition to effects of the primary malignancy itself, numerous factors related to the treatment of malignancy can result in impaired or disrupted fertility. Providers managing male cancer patients at risk for loss of fertility should discuss available fertility preservation options, including sperm cryopreservation when applicable, and consider referral of the patient to fertility preservation specialists when indicated.
No potential conflicts of interest relevant to this article were reported.