Preservation and restoration of fertility

Currently, men who have testicular cancer have many options available to preserve fertility and potential paternity. The availability of sperm cryopreservation, advances in assisted reproductive techniques (ART), and testicular sperm extraction (TESE) provide the potential for fatherhood for men unable to conceive as a result of testicular cancer treatments. It should be noted that men who have testicular cancer status post chemotherapy have decreased fertilization rates per in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle and a decreased pregnancy rate compared with men who have testicular cancer treated without chemotherapy [56]. Sperm cryopreservation should therefore be recommended to men who have germ cell neoplasms before the initiation of treatment when possible.

Records of 67 couples referred for ART for male factor infertility following treatment of malignancies, including testicular cancer and lymphoma, were reviewed to determine the options used and success of various treatment modalities. Eighty-two percent of men cryopreserved sperm before treatment and 58% of men used cryopre-served sperm for ART. A total of 151 cycles of ART were completed, including 55 intrauterine inseminations (IUI), 82 ICSI, and 14 ICSI-frozen embryo replacements, with a corresponding delivery rate of 11.1%, 30.5%, and 21%, respectively [57]. A separate study evaluating the viability of cryopreserved sperm obtained from men before antineoplastic treatment revealed an overall 18.3% pregnancy rate and 7% IUI, 23% IVF, and 37% ICSI pregnancy rates [58]. In men who have true anejaculation or azoospermia, TESE can provide viable sperm for ICSI. An evaluation of 12 men who had azoospermia status post chemotherapy documented motile spermatozoa in 41.6% of men after TESE [59]. In 17 azoospermic men postchemotherapy, testicular biopsies performed at the time of TESE revealed Sertoli cell only in 76% of patients and hyposper-matogenesis in 24% if patients. Of these patients, 45% had successful sperm extraction that resulted in live births in 22% of couples [60]. The ability to preserve fertility through ART is an option for men who have persistent azoospermia or anejacu-lation after treatment of testicular cancer and cryopreservation should always be recommended to enhance the potential for paternity.

Teratogenic potential

Current cancer treatment regimens and reproductive technologies allow many men to be cancer survivors and new fathers. In the setting of malignant testicular dysgenesis and potentially gonadotoxic therapies, many of these men are concerned regarding the potential risk for increased congenital anomalies. Exposure to eto-poside in mice resulted in disomy, centromeric abnormalities, and increased diploid sperm in comparison with controls [61]. Mice treated with BEP did not demonstrate an increased risk for pregnancy loss, but offspring of mice treated with BEP for 9 weeks had a significantly higher rate of neonatal mortality than offspring of mice treated for only 6 weeks [48].

In humans, assessment of sperm integrity before and after treatment of germ cell neoplasms did not reveal a higher DNA fragmentation index after diagnosis of germ cell tumors in comparison with controls but did reveal a higher DNA fragmentation index up to 2 years after radiotherapy. This increased DNA fragmentation index was not noted after chemotherapy [62]. Fluorescence in situ hybridization (FISH) of semen specimens from five men after BEP treatment revealed a significantly increased frequency of diploidy and disomy 16, 18, and XY in comparison with healthy controls at 6 to 17 months after treatment [63]. Conversely, another study using FISH to assess the risk for disomy for chromosomes 1, 12, X, Y, and XY in men treated with BEP found no increased risk for numerical chromosomal abnormalities [64].

Many retrospective studies involving patient-reported pregnancy outcomes have investigated the risk for early pregnancy loss and perinatal morbidity and mortality in children fathered by men who had testicular cancer and found no increased risk for pregnancy loss or congenital anomalies [65]. Spermon and colleagues [66] sent questionnaires to 305 men who had germ cell tumors from 1982 to 1999, 226 of whom responded to evaluate fertility before and after treatment. Using patient questionnaires, Spermon and colleagues [66] documented a 66% and 43% conception rate in patients attempting to conceive within 1 year before the diagnosis of testicular cancer and after treatment, respectively. The rate of congenital anomalies was approximately 4% before and after treatment of germ cell neoplasms. Given this data regarding the potential for chromosomal abnormalities in the posttreatment period, sperm cryopreservation should be performed before the initiation of gonadotoxic treatment. Additionally, men should be counseled to postpone conception for approximately 12 to 18 months after treatment to minimize the risk for potential fetal anomalies [67].

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