The Effects of the Indazole Carboxylic Acid Derivative, Tolnidamine, on Testicular Function: I

Open Access
Publisher Website
Google Scholar
Abstract
The indazole carboxylic acid derivative, tolnidamine, has marked antispermatogenic activity in several animal species. In this study, we assessed the effect of tolnidamine on rat Sertoli cell function both in vivo and in vitro, using androgen binding protein (r ABP) as a marker. Groups of six male rats were killed 2, 4, 8, 16, 32, 64 hours and 5, 8, and 12 days following tolnidamine administration (250 mg/kg by oral gavage). There was a progressive reduction in both testicular and epididymal weights. Serum FSH levels did not change and LH showed a transient increase between 64 hours and 8 days. Except for an initial increase at 2 hours, there were no changes in serum testosterone. Epididymal rABP concentration and content declined as early as 8 hours, with the lowest values occurring at 5 and 12 days. By 16 hours, there was an increase in testicular rABP, which was also evident at 8 days and 12 days. Within 16 hours after tolnidamine, there was a rise in serum rABP, which persisted until the end of the experiment. When another indazole carboxylic acid derivative, lonidamine, was administered (250 mg/kg), similar changes were evident in epididymal and serum rABP at 32 hours, but the rapid decrease in testicular rABP suggested a different mechanism of action. In another experiment, single oral doses of tolnidamine (50, 100, 250, and 500 mg/kg) were administered to other groups of rats and the animals were killed after 24 hours and 5 days. With increasing doses of tolnidamine, there was a reduction in epididymal rABP concomitant with an increase in testis and serum rABP levels. Since rABP levels in the testis and epididymis change following treatment with tolnidamine, we wished to determine whether this agent had a direct effect on Sertoli cells; this possibility was investigated in vitro. Sertoli cells were prepared from 20-day-old animals and cultured in serum-free medium containing insulin, transferrin, epidermal growth factor, and various concentrations of lonidamine or tolnidamine. By 7 days, there were no significant effects on rABP secretion into the medium with either agent. It can be concluded that a single dose of tolnidamine has a minimal effect on the pituitary Leydig cell axis since there was only a transient increase in serum LH with no alterations in testosterone. In contrast, this drug had a dramatic and rapid effect on seminiferous tubule function as manifested by disruption of the dynamics of rABP secretion. The reduction in epididymal rABP may be best explained by inhibition of the passage of tubular fluid to the epididymis. Obstruction of efferent ductules was unlikely because there was no increase in testicular weight. The increase in testicular rABP was presumably related to accumulation secondary to reduced secretion into, or transport from, the seminiferous tubular lumen. The rise in serum rABP is best explained by increased testicular rABP concentration. The failure to observe a change in rABP concentration during incubation of cultured Sertoli cells with increasing doses of tolnidamine implies a lack of a direct effect of tolnidamine on rABP synthesis, and suggests that this drug primarily alters the kinetics of secretion from the intact tubule.