With improved survival of young men with Hodgkin's disease (HD), as well as other cancers, prevention of secondary toxicities such as sterility are of increasing concern. Two approaches will be taken to minimize the sterilizing side effects of cytotoxic therapies: [1] evaluate the recovery of sperm production following a new clinical protocol for Stages I to III2B that does not employ alkylating agents; [2] understand the mechanisms by which hormonal manipulation protects spermatogenesis in experimental animals form the alkylating agents and pelvic radiation that are currently necessary for the treatment of later stage and recurrent HD in order to extend this protection to man. The effects of the new regimen of NOVP (novantrone, oncovin, vinblastine, prednisone) and radiotherapy for HD on sperm counts in men will be determined by evaluating the kinetics of decline of counts during treatments and the time course of recovery following therapy. The effects of variables, such as testicular radiation dose, on the recovery of sperm production will be evaluated. Testosterone treatment appears to protect spermatogenesis in the rat from cytotoxic damage by procarbazine (PCB) and radiation; however, the mechanism of protection is unknown. The following possible mechanisms will be evaluated by comparison of control and testosterone-treated rats: alterations in stem cell kinetics changes in the amount of DNA damage in spermatogonia, alterations in oxygen levels variation in testicular blood flow, the role of both systemic and intratesticular PCB metabolism, and changes in thiol levels within the testis and within spermatogonia. These studies will employ histology, alkaline elution, radiolabeled tracers, enzymatic and HPLC analysis of metabolites, and flow cytometry. Pretreatment with follicle stimulating hormone (FSH) has been reported to protect spermatogenesis in the monkey from a single dose of radiation. We will utilize available monkeys from other studies to extend this observation to fractionate irradiations.
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