Chronic toxicity and reversibility of antifertility effect of immunizationagainst gonadotropin-releasing hormone in male rats and rabbits

Citation
N. Kumar et al., Chronic toxicity and reversibility of antifertility effect of immunizationagainst gonadotropin-releasing hormone in male rats and rabbits, TOXICOL SCI, 53(1), 2000, pp. 92-99
Citations number
26
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGICAL SCIENCES
ISSN journal
10966080 → ACNP
Volume
53
Issue
1
Year of publication
2000
Pages
92 - 99
Database
ISI
SICI code
1096-6080(200001)53:1<92:CTAROA>2.0.ZU;2-C
Abstract
The chronic systemic toxicity of immunization with gonadotropin-releasing h ormone, conjugated to tetanus toroid (GnRH-TT), was investigated in male ra ts and rabbits in order to start Phase I clinical trials. Groups of rats an d rabbits were immunized with GnRH-TT dissolved in aqueous adjuvant. The an tigen was administered at weeks 0, 4, and 8, followed by boosters to mainta in high antibody titers. At termination (8-9 months after first immunizatio n), twenty rats and ten rabbits exhibiting the highest mean anti-GnRH titer s and all the controls were selected for complete toxicological evaluation. In the rat study, a castrated control group was included for comparison wi th the immunized group. The hematological and serum chemistry parameters of immunized rats and rabbits were not affected in a significant manner. Most of the changes in serum chemistry of immunized rats were also found in cas trated rats, indicating that the changes are most likely due to the withdra wal of androgenic support. The weights of the testes, epididymides, and sex accessory glands were lower in all immunized animals. There was significan t atrophy of the germinal epithelium, which, however, sustained a populatio n of Sertoli cells, spermatogonia, and pachytene spermatocytes. Other morph ological changes in the prostate, seminal vesicles, pituitary, and mammary gland reflected the effect of androgen withdrawal. The decrease in the weig ht of liver, kidney, and heart seen in the immunized rats was also present in castrated rats and was not associated with any histopathological changes . The reversibility of immunization-induced infertility was investigated by mating the rats with normal females. Four months after the start of immuni zation, 9 out of 10 immunized rats were infertile whereas by nine months, a ll rats had regained fertility. Thus, it is concluded that immunization wit h GnRH-TT had no systemic toxicological effects in the adult male rats and rabbits for the period studied. The results also indicated that the GnRH-TT immunization had an antifertility effect in male rats. Fertility was resto red following cessation of immunization and decline in anti-GnRH antibody t iters.