2005 © Oxford University Press
Treatment Options for the Infertile Male With Cancer
Affiliations of authors: Baylor College of Medicine, Department of Urology, Houston, TX
Correspondence to: Larry I. Lipshultz, MD, Baylor College of Medicine, Urology, 6560 Fannin, Suite 2100, Houston, TX 77030 (e-mail: llipshul{at}www.urol.bcm.tmc.edu).
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ABSTRACT |
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 TopNotes Abstract IntroductionSPERM BANKINGSPERM RETRIEVAL METHODSFUTURECONCLUSIONReferences |
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The detrimental effects of cancer on male fertility are multifactorial and may be secondary to the disease process itself or to therapeutic interventions. Patients and their doctors need to be better informed about the options men with cancer have to preserve their fertility status. Sperm banking is a safe and effective means of storing sperm before chemotherapy, radiotherapy, or surgery. Advances in assisted reproductive techniques allow in vitro fertilization to occur with the injection of a single sperm into an egg (IVF-ICSI); consequently, the requirement for the amount of sperm needed from cryopreservation is minimal. Pregnancies have been achieved using IVF-ICSI with cryopreserved sperm from patients with a history of malignancy. Similarly, successful sperm retrieval using testicular sperm extraction combined with IVF-ICSI can be accomplished for men with nonobstructive azoospermia after chemotherapy. New techniques such as spermatogonial cell transplantation offer the potential to restore fertility in patients who have received radiation or chemotherapy.
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INTRODUCTION |
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Survival rates among patients with cancer have improved dramatically in recent years because of advanced diagnostic techniques and improved therapeutic options (1,2). Subsequently, quality-of-life issues have become important to an increasing number of cancer survivors, and especially to men who want to preserve their fertility status. A recent survey conducted by Schover and associates (3) revealed that 51% of men with cancer wanted children in the future, including 77% of men who were childless when their cancer was diagnosed. Although improved chemotherapy regimens have resulted in a lower degree of infertility (4), the incidence of azoospermia after treatment remains high, with only 20%–50% of these men having some recovery of spermatogenesis (5). Because it is difficult to predict which patients with cancer will survive or become sterile after treatment, sperm banking is strongly recommended for all patients with malignant disease who wish to preserve their fertility potential (6).
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SPERM BANKING |
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Before chemotherapy, radiation therapy, or surgery affecting the reproductive system, the patient should initiate and complete the cryopreservation process. Traditionally, the banking of at least three semen samples with an abstinence of at least 48 hours between samples has been recommended. Completion of the process usually requires 5–8 days. Additional samples and longer abstinence periods (72–96 hours) to achieve higher total sperm counts may also be considered.
Frequently, because the need to initiate therapy may be urgent, fewer samples are obtained, and with shorter-interval collection periods. Advances in assisted reproductive technology have recently changed the semen quality parameters necessary for fertilization, obviating the need for a high prefreeze sperm density. In vitro fertilization (IVF) in combination with intracytoplasmic sperm injection (ICSI) allows the injection of a single sperm directly into the cytoplasm of each egg, with the resulting embryos being transferred. Thus, only a few live sperm cells need to survive the freeze–thaw process for the creation of a potentially viable pregnancy. Although cryopreservation and subsequent thawing are associated with a variable loss of sperm viability and motility, 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 (7).
If chemotherapy or radiation treatment has already been initiated, collection and cryopreservation of semen are still feasible during treatment, at least until azoospermia ensues (5). However, the effects of these gonadotoxic agents on sperm are unknown. Experimental animal data indicate that a high incidence of mutagenic effects can be seen in offspring from matings that take place during or right after treatment of the male with chemotherapy or radiation (8). De Mas and associates (9) have reported a significant increase in the frequency of sperm aneuploidy that may be persistent up to 18 months or more after the initiation of chemotherapy. The clinical effect of such an increase in chromosomal abnormalities of sperm remains to be seen. Therefore, cryopreservation should ideally be performed before initiation of chemotherapy or radiotherapy. Otherwise, the patient is advised to wait 12–18 months after the completion of therapy before pursuing fertility.
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SPERM RETRIEVAL METHODS |
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Testicular Sperm Extraction
Previously, patients who were persistently azoospermic after chemotherapy and who did not bank sperm before therapy were considered sterile and able to have children only through adoption or donor insemination. The recent success of testicular sperm extraction (TESE) combined with ICSI for patients suffering from nonobstructive azoospermia (10,11) indicates that the combination offers a potential new treatment option for these couples. In 2001, Chan and associates (12) first reported successful sperm retrieval in 9 of 17 (53%) men with postchemotherapy azoospermia by using TESE in combination with ICSI (12). A total of 20 attempts using TESE-ICSI resulted in clinical pregnancy in three of nine couples (33%) and in live delivery in two of nine couples (22%) (12). No correlation was observed between the outcome of TESE-ICSI and the underlying malignancies treated with chemotherapy, nor with the chemotherapeutic agents used (12). Other investigators have reported similar findings of testicular spermatozoa following TESE in azoospermic men after chemotherapy (13,14) (see Table 1). To date, 14 live births of healthy children have been reported (12–14), indicating that conception is possible after chemotherapy treatment. Although these results are encouraging, couples need to be aware of the potential genetic risks of the procedure because the long-term consequences are unknown.
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Because success has been achieved using TESE for postchemotherapy azoospermic men, Schrader et al. (15) examined the use of TESE to obtain spermatozoa in azoospermic cancer patients before initiation of cytotoxic treatment. In their study of 31 patients (14 with malignant testicular germ cell tumors and 17 with malignant lymphoma), successful sperm recovery was possible in 14 (45%) men (six with testicular tumor and eight with lymphoma). Cryopreserved sperm from two patients with malignant lymphoma were used for IVF-ICSI, resulting in one successful live delivery. Given these encouraging results, the authors concluded that TESE should be considered in select cases as an option for fertility preservation in pretreatment azoospermic cancer patients (15).
Microsurgical Epididymal Sperm Aspiration
For patients with unreconstructable obstructive azoospermia related to surgery affecting the reproductive system, such as a radical prostatectomy, abundant high-quality sperm can be retrieved with microsurgical epididymal sperm aspiration. Cryopreserved sperm obtained by microsurgical epididymal sperm aspiration, when used in conjunction with IVF-ICSI, have been shown to have an excellent fertilization rate (37% per oocyte) and pregnancy rate (40% per couple and 29% per cycle) (16). Identical pregnancy rates have been reported with IVF-ICSI, using freshly aspirated sperm or frozen epididymal sperm (17). For men with preserved testicular function, microsurgical epididymal sperm aspiration is a highly effective technique for retrieving numerous sperm suitable for IVF-ICSI.
Electroejaculation
Some patients with testicular cancer are required to undergo a retroperitoneal lymph node dissection as part of their treatment. In the last 20 years, modified nerve-sparing techniques have reduced the amount and extent of dissection necessary around the lumbar sympathetic fibers, particularly at the hypogastric plexus. Although the goal of the modified retroperitoneal lymph node dissection technique is to preserve ejaculation, up to 50% of patients may experience anejaculation (18). When medical treatment using oral sympathomimetics is unsuccessful in producing emission and ejaculation, electroejaculation has been shown to be an effective treatment option in over 70% of these patients (19). Sperm motility tends to be low after electroejaculation, and when intrauterine insemination is used, the fecundity per cycle is 9%–12% (20,21). IVF-ICSI has recently been shown to be a viable alternative for patients with anejaculation in whom intrauterine insemination has failed, with a median 60% fertilization rate, 15% pregnancy rate per cycle, and 29% pregnancy rate per couple (22).
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FUTURE |
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Stem Cell Research
Currently under investigation is a method to preserve male germ cells by harvesting spermatogonial stem cells—cells that are capable of self-renewal, proliferation, and repopulation of the seminiferous tubules. Enzymatic digestion of the testicular tissue into a single-cell solution is performed before the cryopreservation (23). The spermatogonial stem cells potentially can be transplanted back into the patient's testis after cancer treatment to restore fertility. Encouraging results from germ cell transplantation have been reported in animal studies. Brinster and colleagues reported the first successful transplantation of mouse stem spermatogonia from a donor mouse to a recipient mouse. The endogenous stem spermatogonia of the recipient had been killed with busulfan, and the transplant resulted in restoration of spermatogenesis and fertility (24). Similar success has been reported in rats and larger mammals (25,26). Restoration of spermatogenesis is also possible with cryopreserved cells (27). In addition, it has been estimated that 70% of spermatogonial cells can survive after freezing and thawing (28).
A potential concern related to this technique is the transmission of cancer cells back to the recipients. Systemic diseases such as leukemia can involve the testes, and intratesticular transplantation of testicular cells from leukemic rats can cause leukemia in the recipient rat (29). Efforts have been made to circumvent this potential threat. One approach is to use in vitro maturation of the germ cells and harvest only the mature spermatozoa. This has been accomplished in the mouse by transfecting the donor cells with mTERT, the gene responsible for the production of telomerase that can maintain the cells in culture and aid differentiation into haploid gametes (30). An alternative is to use embryonic stem cells, which are considered pluripotent and may have the capacity to differentiate into germ cells. The validity of this approach was confirmed by Toyooka et al. (31), who cocultured embryonic stem cells with bone morphogenic protein 4–producing cells. The resulting cells can form germ cells when transplanted into the sterile recipient's testicular tubules (31). Significantly more translational research is needed, however, before these advances are applied to the treatment of human male infertility.
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CONCLUSION |
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TopNotesAbstractIntroductionSPERM BANKINGSPERM RETRIEVAL METHODSFUTURECONCLUSIONReferences |
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Sperm cryopreservation is a safe, effective means of preserving fertility and should be offered to all cancer patients before they undergo chemotherapy, radiation, or surgery. Recent advances in assisted reproductive technologies such as IVF-ICSI have reduced the number of cryopreserved sperm necessary for successful fertilization of eggs. Furthermore, sperm extraction is possible from nonobstructive azoospermic cancer patients, providing these men and their partners hope for pregnancy. Exciting research in spermatogonial cell transplantation offers the potential for future therapy to restore fertility in previously infertile men.
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NOTES |
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L. I. Lipshultz is a speaker on clinical research for Bayer/GlaxoSmithKline, Lilly/ICOS, and Pfizer.
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REFERENCES |
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