Avoiding Toxins Including Spermatotoxic Medications

Gillian Stearns, MD; Paul J. Turek, MD


Semin Reprod Med. 2013;31(4):286-292. 

In This Article


Chemotherapy is a necessary treatment for many malignancies including Hodgkin lymphoma, testicular cancer, and leukemia. The agents used in chemotherapy are often damaging to both germ cells and Sertoli cells. Leydig cells are less affected by chemotherapy.[1] It is common to see azoospermia immediately posttreatment with associated decreased testosterone and elevated LH levels. The ability to regain spermatogenesis depends on the agent, its dosage, and the duration that it is used.[1,5] Due to the possibility of permanent disruption of spermatogenesis, one should always offer sperm cryopreservation before chemotherapy.[1]

Alkylating agents are most damaging to sperm, including cyclophosphamide, busulfan, chlorambucil, cisplatin, procarbazine, and melphalan.[5] Toxicity appears to correlate to total dose of the agent. Dosage adjustments have been made to attempt to decrease spermatotoxicity, but it is often difficult to calculate total dose and correlate this with fertility years later.[18] In one study, 45% of men reported azoospermia posttreatment, but this figure was 90% with the highest dose of cyclophosphamide.[5] Recovery from azoospermia is variable and can take up to 5 years. Prepubertal boys may be less sensitive to the gonadotoxic effect of these agents, but this again may be dose related.[18] Kenney et al[61] looked at 17 adults who had been treated with vincristine, actinomycin, cyclophosphamide, and/or doxorubicin to determine lasting gonadal effects of chemotherapy. Only two were found to have a normal sperm count posttreatment and they had received the lowest doses of cyclophosphamide.[61]

Cisplatin may also cause irreversible impairment of spermatogenesis, but recovery may begin as early as 2 years after treatment.[62] A study of self-reported fertility 12 years after chemotherapy for testis cancer (two to four cycles of cisplatin-based chemotherapy) showed that some patients had indeed achieved natural fertility, but the rate of fertility was directly proportional to chemotherapy dose.[63] A 2005 study by Brydøy et al found the paternity rate in these patients to be 71% after chemotherapy without use of assisted reproductive therapy.[64] Methotrexate has not been shown to affect sperm count, motility, or morphology as profoundly as other chemotherapeutic agents.[18]

The addition of busulfan to cyclophosphamide chemotherapy increases the chances of spermatogenic failure. Vinca alkaloids typically arrest spermatogenesis and have profound effects on sperm motility. Other combinations of chemotherapy can be even worse, as the synergistic effects associated with such therapies induce longer lasting effects on the reproductive system than single-agent therapy.[18] Treatment with adriamycin, vincristine, methotrexate, and 6-MP renders 16% of men with azoospermia up to 11 years after discontinuation of treatment.[62] Spermatogenic recovery after cyclophosphamide and busulfan preparation for bone marrow transplant occurred less than 20% of cases. This is confirmed in animal models of CHOP administration, in which permanently decreased testicular weights and sperm counts occurred in rats.[62] Many Web sites exist, including FertileHope.com, to help patients and their care providers determine future fertility rates based on cancer type and therapy received.[65]