Health&Care: Single-agent chemotherapy
Single-agent chemotherapy
The alkylating agents have been the single agents most widely studied for their effects on reproductive function. There are, however a few reports of other drugs used in isolation having a detrimental influence on fertility.
Methotrexate
Adult men
Methotrexate is an antimetabolite that acts as a folinic acid antagonist and in general appears to have little effect on spermatogenesis. It has been proposed that there is a significant barrier to the passage of methotrexate across the blood-seminiferous tubule barrier, although reports have demonstrated severe reductions in sperm counts in certain individuals. This is probably related to the high dose used in these patients. The drug acts on tissues with a high mitotic activity and, therefore, affects the rapidly dividing primitive sperm cells, notably the spermatogonia and spermatocytes. In some cases, the drug has been administered to non-cancer patients. One report describes a man treated with methotrexate for psoriasis, with a total dose of 800 mg.
Serial analyses of seminal fluid demonstrated low sperm counts and a high number of morphologically abnormal forms. These disturbances resolved after the drug was discontinued. Recommencing therapy was associated with another reduction in count. Despite this, gonadotrophin levels remained normal. Another study looked at high-dose methotrexate in men being treated for osteosarcoma. Approximately 50% developed severe oligozoospermia associated with raised FSH levels during or immediately after treatment. Sperm concentration and hormone levels both returned to normal after the completion of therapy.
Three cases of erectile dysfunction and inability to ejaculate have also been recorded in men receiving 12.5 mg methotrexate weekly for arthritis. Normal sexual function returned on discontinuing the drug though at the expense of worsening arthritis.
Adult women
In women, high-dose methotrexate appears to have no effect on ovarian function. It is frequently used in the chemotherapy of choriocarcinoma. Rustin et al, noted that 187 of 217 women who wished to become pregnant after methotrexate therapy had children. Interestingly, 37 of the women who did succeed in having a baby had also received cyclophosphamide.
Other single agents
Corticosteroids
Early studies suggested that prednisolone at a dose of 30 mg/day for 15 days causes reduced sperm counts and motility. This is associated with evidence of spermatogenic arrest at testicular biopsy. Full recovery had not occurred 6 months after the cessation of a 30 day trial. Sperm abnormalities have also been demonstrated in 10 men using topical cortisone for psoriasis. The significance of these earlier reports, however, must be questionable. Higher dosage steroid regimens are now normal practice in the therapy of male infertility resulting from antisperm antibodies, and no detrimental effect on sperm parameters has been reported.
Mitotane
Mitotane has been used to treat adrenocortical carcinoma. One case report describes a patient who developed impotence as a result of testicular failure at the time of mitotane therapy. Testicular biopsy showed atrophy of seminiferous tubules but normal Leydig cells. Libido gradually improved and testosterone and gonadotrophin levels normalised over the next 4 years.
Vincristine
An assessment of 55 adult males who had been treated in childhood for various forms of malignancy showed that 28 (51%) were azoospermic. Although many different therapeutic regimens had been used, the authors showed by a multivariate statistical analysis that the use of vincristine had the most significant independent effect on the risk of azoospermia. The risk was five times greater than in patients who did not receive vincristine.
