Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide
Grima,Josephine; Silvestrini,Bruno; Cheng,Chuen-yan
Biology of Reproduction 64(5): 1500-1508
Publication date: 2001
The oral male contraceptive agent 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide(AF2364) is a new analogue of indazole-carboxylic acid. AF2364was orally administered to rats at 50 mg/kg body weight onceweekly for five consecutive weeks. The effects on fertilityefficacy, hormonal profile, organ weights, tissue morphology,and serum microchemistry were examined. Complete infertilitywas noted in rats 29 days after the initial dose of AF2364 andcontinued until 90 days. Fertility resumed in 25% of the groupafter 104 days and had resumed in 75% of the rats by the lastmating at 197 days. Morphological examination of the testisshowed rapid exfoliation of elongated spermatids and the generationof large multinucleated cells 6 days after the first treatment,with depletion of most germ cells after 40 days. Normal spermatogenesiswas noted in 95% of the tubules in the animals that were fertileat 210 days. Morphological analysis of the epididymal compartmentsrevealed reduced lumen size, whereas the prostate exhibitedan increase in the glandular lumen with a reduction in epitheliumheight. No morphological changes were detected in the kidney,liver, and cerebrum by light microscopy. Kidney and liver function,as evaluated by serum chemistry, were not affected by the drugtreatment. AF2364 did not alter the levels of FSH, and onlyminimal changes were noted for LH and testosterone, suggestingthat the hypothalamic-pituitary-testicular axis was not affected.These results illustrate the potential of AF2364 as a male contraceptive.