Male Gonadal Toxicity

Gonadal irradiation and alkylating agent chemotherapy may produce testicular Leydig cell or germ cell dysfunction, with risk related to cumulative dose of both modalities.

Hypoandrogenism associated with Leydig cell dysfunction may manifest as lack of sexual development; small, atrophic testicles; and sexual dysfunction. Hypoandrogenism also increases the risk of osteoporosis and metabolic disorders associated with chronic disease.[5,6]

Testicular Leydig cells are relatively resistant to treatment toxicity compared with testicular germ cells. Survivors who are azoospermic after gonadal toxic therapy may maintain adequate testosterone production.[7-9]

Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[10,11]

The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Pubertal status is not protective of chemotherapy-associated gonadal toxicity.[8,9]

Chemotherapy regimens that do not include alkylating agents are not associated with male infertility. These regimens include doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine (ABVD); doxorubicin (Adriamycin), bleomycin, vincristine, etoposide (ABVE); vincristine (Oncovin), etoposide, prednisone, doxorubicin Adriamycin (OEPA); or vincristine, doxorubicin (Adriamycin), methotrexate, prednisone (VAMP).

Prednisone and cyclophosphamide (ABVE-PC) and cyclophosphamide, vincristine, prednisone, dacarbazine (OEPA-COPDAC) are titrated to limit alkylating agent dose to below the usual threshold associated with male sterility. Investigations evaluating germ cell function in relation to single alkylating agent exposure suggest that the incidence of permanent azoospermia will be low if the cyclophosphamide dose is less than 7.5 g/m2.[9,12]

Chemotherapy regimens that include more than one alkylating agent, usually procarbazine in conjunction with cyclophosphamide (i.e., cyclophosphamide, vincristine [Oncovin], prednisone, procarbazine [COPP]), chlorambucil, or nitrogen mustard (MOPP), confer a high risk of permanent azoospermia if treatment exceeds three cycles.[13,14]