Causes of Male infertility - Gonadotoxins

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A. Radiation
The effects of radiotherapy on sperm production are well described. They are derived mainly from a series of remarkable experiments performed during the “atomic age” but only recently published. In a study of healthy prisoners in Oregon and Washington in the 1960s, Clifton and Bremner (1983) examined the effects of ionizing irradiation on semen quality and spermatogenesis. Before a Vasectomy, each of 111 volunteers was exposed to different levels of radiation, from 7.5 to 600 cGy. Sperm counts were analyzed weekly and each prisoner served as his own control. There was a distinct dose-dependent, inverse relationship between irradiation and sperm count. A significant reduction in sperm count was observed at 15 cGy, and sperm counts were temporarily abolished at 50 cGy. Azoospermia was induced at 400 cGy in 4 of 5 patients; this persisted for at least 40 weeks. Despite these profound effects, sperm counts rebounded to preirradiation levels in most patients during recovery.

From examination of testis tissue after irradiation, it was concluded that spermatogonia are the germ cells most sensitive to irradiation. Given the dramatic sensitivity of testis tissue to irradiation, subsequent studies have focused on the “scatter” to testes of men undergoing radiation therapy for cancer. In patients subjected to abdominal radiation with gonadal shielding, the estimated mean unintended gonadal exposure was approximately 75 cGy. There does not appear to be an increase in congenital birth defects in offspring of irradiated men.

B. Drugs
Medications are usually tested extensively for their potential as reproductive hazards before marketing. Despite this, it is wise to discontinue unnecessary medications that can be safely stopped during attempts to conceive. A list of gonadotoxic medications can be found in Table 42-13. These can result in infertility by various mechanisms. Ketoconazole, spironolactone, and alcohol inhibit testosterone synthesis, whereas cimetidine is an androgen antagonist. Recreational drugs such as marijuana, heroin, and methadone are associated with lower testosterone levels. Certain pesticides, like dibromochloropropane, are likely to have estrogen-like activity.

Cancer chemotherapy is designed to kill rapidly dividing cells; an undesired outcome is the cytotoxic effect on normal proliferating tissues. Differentiating spermatogonia appear to be the germinal cells most sensitive to cytotoxic chemotherapy. Alkylating agents such as cyclophosphamide, chlorambucil, and nitrogen mustard are the most toxic agents. The toxic effects of chemotherapeutic drugs vary according to dose and duration of treatment, type and stage of disease, age and health of the patient, and baseline testis function. Despite this toxicity, the mutagenic effects of chemotherapy agents does not appear to be significant enough to increase the chance of congenital defects or genetically linked diseases among offspring of treated men. However, patients should wait at least 6 months after chemotherapy ends before attempting to conceive.

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