Chronic toxicity and reversibility of antifertility effect of immunization against gonadotropin-releasing hormone in male rats and rabbits
Kumar,Narender; Savage,Toyin; DeJesus,William; Tsong,Yun-yen; Didolkar,Ashok K.; Sundaram,Kalyan
Toxicological Sciences 53(1): 92-99
Publication date: 2000
The chronic systemic toxicity of immunization with gonadotropin-releasinghormone, conjugated to tetanus toxoid (GnRH-TT), was investigatedin male rats and rabbits in order to start Phase I clinicaltrials. Groups of rats and rabbits were immunized with GnRH-TTdissolved in aqueous adjuvant. The antigen was administeredat weeks 0, 4, and 8, followed by boosters to maintain highantibody titers. At termination (8-9 months after firstimmunization), twenty rats and ten rabbits exhibiting the highestmean anti-GnRH titers and all the controls were selected forcomplete toxicological evaluation. In the rat study, a castratedcontrol group was included for comparison with the immunizedgroup. The hematological and serum chemistry parameters of immunizedrats and rabbits were not affected in a significant manner.Most of the changes in serum chemistry of immunized rats werealso found in castrated rats, indicating that the changes aremost likely due to the withdrawal of androgenic support. Theweights of the testes, epididymides, and sex accessory glandswere lower in all immunized animals. There was significant atrophyof the germinal epithelium, which, however, sustained a populationof Sertoli cells, spermatogonia, and pachytene spermatocytes.Other morphological changes in the prostate, seminal vesicles,pituitary, and mammary gland reflected the effect of androgenwithdrawal. The decrease in the weight of liver, kidney, andheart seen in the immunized rats was also present in castratedrats and was not associated with any histopathological changes.The reversibility of immunization-induced infertility was investigatedby mating the rats with normal females. Four months after thestart of immunization, 9 out of 10 immunized rats were infertilewhereas by nine months, all rats had regained fertility. Thus,it is concluded that immunization with GnRH-TT had no systemictoxicological effects in the adult male rats and rabbits forthe period studied. The results also indicated that the GnRH-TTimmunization had an antifertility effect in male rats. Fertilitywas restored following cessation of immunization and declinein anti-GnRH antibody titers.