Partial prevention of procarbazine induced germinal cell aplasia in rats by sequential GnRH antagonist and testosterone administration.
The present study examined the feasibility of using a combination of gonadotropin releasing hormone antagonist (GnRH-A) and testosterone in the prevention of procarbazine induced germinal aplasia. Daily injections of GnRH-A or vehicle were given to adult male rats for 21 days prior to procarbazine (PCB) administration and continued until 2 days after the second of two doses of procarbazine (200 mg/kg i.p.) given 1 week apart. One group of rats receiving GnRH-A and PCB was given s.c. two 5-cm testosterone capsule (TC) implants (inside diameter, 3.5 mm) immediately following the second dose of PCB. Eight weeks after the last PCB treatment, more than 99% of the seminiferous tubular cross-sections of rats receiving PCB alone were devoid of spermatogenic activity. Spermatogenesis in PCB injected animals receiving GnRH-A pretreatment alone was abortive but was partially preserved when exogenous testosterone was given following PCB administration. At 16 weeks, spermatogenesis was absent in all PCB treated animals and was only observed in less than 1% of the tubular cross-sections of the PCB treated rats receiving GnRH-A pretreatment alone. On the other hand, active spermatogenesis was noted in 68% of the tubular cross-sections, and complete spermatogenesis was noted in four of the five PCB treated rats receiving both GnRH-A pretreatment and subsequent TC implantation. At the time of sacrifice, testicular testosterone concentrations in animals receiving TC implants were below 10% of normal levels, while both serum and testicular testosterone content were increased in PCB treated animals with or without GnRH-A pretreatment. Concomitantly, testicular androgen binding protein content remained suppressed and serum androgen binding protein was elevated, indicating a prolonged defect in Sertoli cell function. These lesions were prevented by GnRH-A pretreatment. The present study demonstrates that GnRH-A pretreatment and subsequent TC implantation resulted in restoration of complete spermatogenesis in adult male rats given a 400-mg/kg cumulative dose of PCB. It is postulated that GnRH-A may ameliorate PCB induced Sertoli cell dysfunction and/or stimulate the number of spermatogonia to provide more proliferating cells ready for repopulation of the germinal epithelium following PCB injury. The differentiation of these spermatogonia was further supported by exogenous testosterone through certain unknown local mechanisms, resulting in the completion of spermatogenesis.
D000727:Androgen-Binding Protein / Q000032:analysis; D000818:Animals; D004347:Drug Interactions; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011344:Procarbazine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013739:Testosterone / Q000494:pharmacology*
D000727:Androgen-Binding Protein; D007987:Gonadotropin-Releasing Hormone; D011344:Procarbazine; D013739:Testosterone; C036959:LHRH, Ac-dehydro-Pro(1)-4-F-Phe(2)-Trp(3,6)-; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone