Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis

The three currently available male contraceptive approaches are 1) the barr ier method such as the condom, 2) hormonal methods by disrupting the pituit ary-testicular axis so as to impair spermatogenesis, and 3) immunological m ethods by preparing vaccines against male-specific antigens. We hereby desc ribe an alternative approach in which attachments of developing germ cells onto the seminiferous epithelium are disrupted, thereby inducing their prem ature release into the tubular lumen. This in turn leads to infertility. A panel of analogues based on the core structure of 1-(2,4-dichlorobenzyl)-in dazole-3-carboxylic acid was synthesized. These compounds were subjected to an in vivo screening assay assessing their effects in inducing the express ion of testin, a testicular marker whose expression correlates with the int egrity of Sertoli-germ cell junctions. An induction of testin expression in the testis signifies a disruption of Sertoli-germ cell junctions that is f ollowed by depletion of germ cells from the seminiferous epithelium. Two co mpounds, namely 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) and 1-(2,4-dichlorobenzyl)-indazole-3-acrylic acid (AF-2785), were identifi ed that caused detachment of germ cells, in particular round and elongated spermatids, from the epithelium inducing their premature release into the t ubular lumen as confirmed by histological analysis. Adult rats receiving se veral oral doses of either one of these compounds became infertile within 3 -7 wk after the epididymal sperm reserve was exhausted. Depending on the do sing of the administered compound, rats became infertile for 4-14 wk before their fertility gradually bounced back, illustrating the reversibility and efficacy of these new compounds. Also, these compounds did not appear to i mpair the hypothalamus-pituitary-testicular axis because the serum levels o f LH, FSH, and testosterone of the treated animals did not change significa ntly when compared to control rats. in addition, results of serum microchem istry illustrate that liver and kidney function was not affected in animals treated with both compounds.