Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide

The oral male contraceptive agent 1-(2,4-dichlorobenzyl)-indazole-3-carbohy drazide (AF2364) is a new analogue of indazole-carboxylic acid. AF2364 was orally administered to rats at 50 mg/kg body weight once weekly for five co nsecutive weeks. The effects on fertility efficacy, hormonal profile, organ weights, tissue morphology, and serum microchemistry were examined. Comple te infertility was noted in rats 29 days after the initial dose of AF2364 a nd continued until 90 days. Fertility resumed in 25% of the group after 104 days and had resumed in 75% of the rats by the last mating at 197 days. Mo rphological examination of the testis showed rapid exfoliation of elongated spermatids and the generation of large multinucleated cells 6 days after t he first treatment, with depletion of most germ cells after 40 days. Normal spermatogenesis was noted in 95% of the tubules in the animals that were f ertile at 210 days. Morphological analysis of the epididymal compartments r evealed reduced lumen size, whereas the prostate exhibited an increase in t he glandular lumen with a reduction in epithelium height. No morphological changes were detected in the kidney, liver, and cerebrum by light microscop y. Kidney and liver function, as evaluated by serum chemistry, were not aff ected by the drug treatment. AF2364 did not alter the levels of FSH, and on ly minimal changes were noted for LH and testosterone, suggesting that the hypothalamic-pituitary-testicular axis was not affected. These results illu strate the potential of AF2364 as a male contraceptive.