Does Testosterone Prevent Cyclophosphamide-Induced Azoospermia?


Synopsis: In a small randomized study, testosterone given once every two weeks permitted the recovery of normal sperm counts after six months off chemotherapy in five men who received monthly boluses of cyclophosphamide at 15 mg/kg.

Source: Masala A, et al. Ann Intern Med 1997;126: 292-295.

Cytotoxic drugs are increasingly being used to treat conditions other than cancer, including autoimmune disorders in which they are administered chronically. A major side effect of alkylating agents that influences their clinical use is the development of essentially permanent azoospermia in treated men. Masala and colleagues conducted a very small clinical trial to evaluate the capacity of testosterone to prevent cyclophosphamide-induced azoospermia in men being treated for eight months for nephrotic syndrome.

Five patients received daily oral cyclophosphamide (150 mg/d), and 10 received monthly intravenous boluses at 15 mg/kg. Half of the latter group received 100 mg testosterone intramuscularly every 15 days beginning one month before the first dose of cyclophosphamide and continuing until the cyclophosphamide was stopped. All 10 patients who did not receive testosterone became azoospermic, and only one had return of normal sperm count. By contrast, all five men who received testosterone developed azoospermia but had normal sperm count recovery by six months after cessation of cyclophosphamide.


It would be a clinical development of major importance if alkylating agent-induced azoospermia could be prevented or reversed. Testosterone reduces the levels of gonado-trophins and, thus, may permit the germinal cells of the testes to rest during administration of alkylating agents. Testosterone itself may induce azoospermia or oligospermia. The data presented in this paper suggest that recovery of spermatogenesis is possible if the germinal cells are not actively producing sperm during exposure.

Of course, the doses of cyclophosphamide used in this study are small compared to those used most frequently in patients with cancer. However, it remains a significant breakthrough that patients who require immunosuppressive therapy and who do not have a malignant disease might not have to become azoospermic to accept effective treatment of their primary disorder. Furthermore, additional work needs to be done to see just how high a dose of cyclophosphamide can be given and still see recovery when testosterone is administered concurrently. If the threshold dose is too low, there may be additional endocrine manipulations to more fully suppress gonadotrophins during chemotherapy. Another line of investigation that might be fruitful is to try to understand why doxorubicin and vinblastine, agents that one might predict would have significant adverse effects on spermatogenesis, are relatively nontoxic to the testes.