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We had previously found that 2,4-diaminopyrimidines affected spermatogenesis, possibly through the inhibition of testicular dihydrofolate reductase (DHFR). The current study examined the effects of etoprine, a highly lipophilic 2,4-diaminopyrimidine that is also a potent DHFR inhibitor, on the fertility of male mice at various dosages (0.1-50 mg/kg/day) for 55 days and male rats at 5 mg/kg/day for 65 days. Two other substituted diaminopyrimidines were tested at dosages of 50 mg/kg/day for 55 days. Results of breeding trials along with assessment of various parameters indicative of male fertility were noted. We found that of the compounds tested, etoprine is a potent antifertility agent that causes complete infertility at doses of > or = 5 mg/kg/day in mice with a threshold of effectiveness occurring between 1 and 5 mg/kg/day. The antifertility action of etoprine may be related to its capacity to inhibit testicular DHFR and its high degree of lipophilicity.

Ketoconazole has been shown to reduce steroidogenesis by inhibiting the cytochrome P-450 enzymes in these pathways. This finding, along with the observation that the compound reduces sperm motility, led us to study the effectiveness of ketoconazole as a male contraceptive agent administered in acute and chronic studies of both rats and mice. Four hours after a single administration, male rats showed significant reductions in both serum testosterone and corticosterone levels that completely recovered (testosterone) or nearly recovered (corticosterone) 24 hours after administration. Chronic administration of ketoconazole to male rats and mice resulted in steroid levels comparable with those of control animals. Epididymal sperm motility was only slightly reduced in male mice 4 hours after administration of the drug. No effect on sperm motility was noted after chronic administration in either species studied. In vitro exposure of epididymal sperm to ketoconazole resulted in a significant reduction of sperm motility. Breeding trials after ketoconazole administration resulted in normal fertility and fecundity even at the highest dosage studied. The lack of correlation between steroid levels and sperm immobilization, along with rapid in vivo and in vitro effects on sperm motility, suggests that the reduction in sperm motility is not related to a decrease in steroid levels. From these data, the authors conclude that ketoconazole is probably not a viable approach to the development of a male contraceptive.

Unilateral spermatic cord torsion causes damage to the contralateral testis in humans and animals models. It is now known, however, at what age an animal's reproductive capacity is most susceptible to this type of trauma. To determine if the animal's age is a factor in its susceptibility to reproductive damage, rats at 30 to 70 days of age were subjected to unilateral spermatic cord torsion. Rats of the same ages underwent sham surgery and served as controls. The animals were allowed to recover from the surgery and to attain puberty before a period of fertility testing. Fertility, serum testosterone, organ weight, and testicular histologic data were obtained after the breeding period. Our data indicate that animals undergoing torsion at the youngest (30 days) and oldest (70 days) ages exhibited no change in the parameters studied. Animals between the ages of 35 and 50 days are highly susceptible to reproductive damage due to unilateral spermatic cord torsion, and the 35-day-old animals exhibit the most susceptibility. The stages of testicular development occurring during this period are such that damage to one testicle will result in degeneration of both organs. However, once the animal is older than 50 days, its reproductive capacity is not affected by spermatic cord torsion. The specific period of susceptibility in the development of human testes is yet to be defined.

Unilateral spermatic cord torsion results in contralateral degeneration and reduced fertility in the prepubertal male rat. This study was conducted to investigate the use of immunosuppression with cyclosporine and prednisone to prevent these untoward effects. Thirty-five-day-old male rats were subjected to 720 degrees unilateral spermatic cord torsion of 9 hours duration. At the time of detorsion, animals were given a subcutaneous injection of i) cyclosporine, ii) prednisone, or iii) cyclosporine combined with prednisone. Control groups included: i) animals undergoing orchiectomy of the ipsilateral testis following the torsion period, ii) hemicastration in the absence of torsion and iii) sham surgery. Orchiectomy at the end of the torsion period prevented the torsion induced reduction of fertility, contralateral seminiferous tubule diameter and testis weight. Treatment with cyclosporine combined with prednisone significantly increased these parameters above detorsion alone. These data indicate that short term immunosuppression with cyclosporine alone or in combination with prednisone limits the adverse effects of unilateral spermatic cord torsion as does removal of the damaged organ at the end of the torsion period.