Lupron depot prevention of antispermatogenic/antifertility activity of the indenopyridine, CDB-4022, in the rat.
The goals of this study were to determine the CDB-4022 dose-response relationship for induction of acute decreases in testicular weight and germ cell depopulation in rats; establish the threshold dose of CDB-4022 required to induce infertility; and investigate whether CDB-4022-induced testicular damage could be prevented by a GnRH agonist (Lupron Depot). Reduction of testis weight and germ cell depopulation were observed 7 days after a single oral dose of 1 mg CDB-4022/kg, whereas 0.5 mg/kg had no observable effect. These effects were maximal at 12.5 or 25 mg CDB-4022/kg. After a single oral dose of either 2.5 or 5 mg/kg, CDB-4022 induced infertility in five of five treated rats by Week 5, whereas only one of five males was rendered infertile at a dose of 1 mg/kg. Proven fertile male rats (6/group) were treated with vehicle, CDB-4022 alone (2.5 mg/kg on Day 0), CDB-4022 plus Lupron Depot (on Weeks -1, 2, 5, and 8), or Lupron Depot alone. Control males demonstrated normal fertility throughout a 32-wk cohabitation period. Five of six rats were rendered transiently infertile with Lupron Depot alone, but all recovered fertility. CDB-4022 treatment resulted in infertility in all six rats, and only one of six regained fertility. Combined treatment also caused infertility in all six rats, but four of six recovered fertility (P = 0.08 compared to CDB-4022 alone). Testicular weight was decreased in the three treatment groups compared to vehicle controls; testicular weights were ranked from highest to lowest as follows: vehicle > Lupron Depot > Lupron Depot + CDB-4022 > CDB-4022. The tubule differentiation index of Lupron Depot-treated rats (96 +/- 4%) was not different from vehicle-treated rats (100%). CDB-4022 treatment decreased the number of differentiating tubules (15 +/- 8%). Lupron Depot plus CDB-4022 treatment resulted in a greater number of differentiating tubules (53 +/- 12%) than CDB-4022 alone, but this was still lower than vehicle- or Lupron Depot-treated rats. These data indicate that 2.5 mg/kg of CDB-4022 was the oral threshold dose that caused testicular damage rendering the majority of adult male rats permanently infertile within the study interval; 12.5 mg/kg of CDB-4022 induced maximal testicular damage. Suppression of gonadotropins and/or testosterone production by treatment with Lupron Depot before and after CDB-4022 prevented the CDB-4022-induced irreversible testicular damage.
Hild
S A
SA
BIOQUAL, Inc., Rockville, Maryland 20850, USA. sahild@compuserve.com
Meistrich
M L
ML
Blye
R P
RP
Reel
J R
JR
D000818:Animals; D000988:Antispermatogenic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003270:Contraceptive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D005300:Fertility Agents, Female / Q000008:administration & dosage / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D016729:Leuprolide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D013737:Testis / Q000166:cytology / Q000187:drug effects
D000988:Antispermatogenic Agents; C435918:CDB 4022; D003270:Contraceptive Agents; D003692:Delayed-Action Preparations; D005300:Fertility Agents, Female; D007192:Indenes; D010880:Piperidines; D016729:Leuprolide