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Late Effects of the Reproductive System

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    Administration of higher radiation doses, such as 2,400 cGy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both sterilization and Leydig cell dysfunction.[11] Craniospinal irradiation produced primary germ cell damage in 17% of 23 children with ALL,[12] but in none of four children with medulloblastoma.[13] Total-body irradiation ([TBI] 950 cGy to 1575 cGy) and cyclophosphamide (60 mg/kg/day for 2 days) produced azoospermia in almost all men.[14]

    Cumulative alkylating agent dose is an important factor in estimating the risk of testicular germ cell injury, but limited studies are available that correlate results of semen analyses in clinically well-characterized cohorts. A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial radiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.[15] Combination chemotherapy that includes an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium.[16,17,18,19,20] Azoospermia occurred less frequently in adults following treatment with two, rather than six, cycles of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone).[21] Elevation of the basal follicle-stimulating hormone (FSH) level, reflecting impaired spermatogenesis, was less frequent among patients receiving two courses of OPPA (vincristine, procarbazine, prednisone, doxorubicin) than among those who received two courses of OPPA in combination with two or more courses of COPP (cyclophosphamide, vincristine, procarbazine and prednisone).[22]

    Most studies suggest that procarbazine contributes significantly to the testicular toxicity of combination chemotherapy regimens. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported following treatment with MOPP.[23] Most studies suggested that prepubertal males were not at lower risk for chemotherapy-induced testicular damage than were postpubertal patients.[17,24,25,26]

    Male survivors of non-Hodgkin lymphoma who underwent pelvic radiation therapy and received a cumulative cyclophosphamide dose greater than 9.5 g/m2 were at increased risk for failure to recover spermatogenesis;[27] in survivors of Ewing and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.[28] Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide prior to undergoing bone marrow transplantation (BMT) for aplastic anemia.[14] Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[29,30,31]

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