Pyrimethamine: an approach to the development of a male contraceptive

Abstract

With the human population of the world currently more than 5.2 billion and growing at an explosive rate, the need for additional forms of readily available contraception appears paramount. To date, contraception techniques in the male have been very limited. The present study demonstrates the ability of pyrimethamine (PYR) to cause spermatogenic arrest and male infertility in mice in a dose-dependent manner. Furthermore, upon cessation of drug administration all animals returned to normal fertility status. It is also suggested that the action of PYR is due to its antifolate action. Thus, PYR represents another approach toward development of a male contraceptive.

PIP: Pyrimethamine's antifertility effects in the male mouse suggest that this agent has potential as a male contraceptive. This dihydrofolate reductase inhibitor was administered to 72 adult male Swiss-Webster mice over a 50-day period at dosages ranging from 10-200 mg/kg/day. During the last 10 days of drug administration, the study mice were exposed to 3 female mice who underwent 2 reproductive cycles. The female mice were examined for gravidity 19 days after the onset of the breeding cycle. Male infertility was dose-dependent, with no pregnancies occurring among the partners of mice who received the maximum dosage of pyrimethamine. Also inversely proportional to dosage were the number and motility of epididymal sperm in the treated mice and mean seminiferous tubule diameter and testicular and epididymal weights. Time course analysis revealed that the drug begins to exert its antifertility effect 33 days after administration and nearly complete infertility is achieved with 50 days, suggesting that pyrimethamine acts on early-midspermatogenesis. All mice returned to normal fertility status 44 days after treatment ended, and epididymal sperm reserves, sperm motility, and testicular and epididymal weights also returned to baseline values within this time period. Of particular interest was the finding that when pyrimethamine was administered to another group of mice for 80 days, infertility was significantly reduced beyond that achieved in 50 days, yet there were no further effects on testicular epididymal function. It would appear that pyrimethamine's mechanism of action is its antifolate action, with the main effect occurring on the testes rather than the epididymis.