The Effects of Chronic Administration of Pyrimethamine on Spermatogenesis and Fertility in Male Rats

Abstract

ABSTRACT: The present study examines whether the antifertility effects of pyrimethamine (PYR), an inhibitor of dihydrofolate reductase, are mediated by a reduction in intratesticular testosterone (T) concentrations or whether PYR exerts its effect by a cytotoxic insult to spermatogenic cells that is independent of intratesticular testosterone. Adult male rats were treated daily with 100 mg/kg (n = 16) or 400 mg/kg (n = 16) of PYR in honey for 8 weeks. Control rats (n = 16) received honey without PYR. Eight weeks after treatment, five rats from each PYR‐treated group and five control rats were mated with normal cycling female rats, and fertility was assessed. These rats were euthanized after the fertility trial; testis weight, testicular sperm, and epididymal sperm counts were determined, and serum levels of T, LH, FSH, and seminiferous tubule fluid T (STF‐T) concentrations were measured by RIA. Testes from three rats per group were perfusion‐fixed for histological evaluation. PYR was discontinued in the remaining rats for 8 weeks and similar parameters were evaluated after 8 weeks of recovery. PYR (100 mg/kg/day) treatment for 8 weeks did not have any effects on organ weights, testicular and epididymal sperm counts, and hormone levels when compared to controls. In contrast, PYR (400 mg/kg/day) treatment significantly reduced testis and epididymis weights, testicular and epididymal sperm counts, and fertility. Despite these effects, serum T, LH, FSH, and STF‐T concentrations were not altered. In rats treated daily with 400 mg/kg PYR, qualitative analysis of the tubules in stage VII and VIII of spermatogenesis revealed a decline in pachytene spermatocytes and round spermatids as well as atrophy of approximately 30% of the seminiferous tubules. The effect was not seen in animals treated with 100 mg/kg. Eight weeks after cessation of treatment, the testis and epididymis weights, sperm counts, and fertility were restored to normal in all PYR‐treated rats. These results indicate that: (1) PYR exerts a direct cytotoxic effect on the seminiferous epithelium, (2) PYR's effect is independent of pituitary LH, FSH, and intratesticular T concentrations; and (3) the effect is completely reversible upon cessation of treatment.