Rat prostatic weight regression in reaction to ketoconazole, cyproterone acetate, and RU 23908 as adjuncts to a depot formulation of gonadotropin-releasing hormone analogue.
The effects of the s.c. administration of a depot formulation of the luteinizing hormone-releasing hormone (LHRH) analogue Zoladex were studied in normal male rats, alone and in combination with three drugs with "antiandrogenic" action (ketoconazole, cyproterone acetate, and RU 23908) on prostatic weight and on circulating hormone levels in order to investigate whether these antiandrogens might prevent the LHRH-A-induced initial increase in these parameters. These effects were compared with those caused by surgical castration. In addition the effects of the antiandrogens on the activity of the hypothalamic-pituitary-adrenal axis were investigated. The depot LHRH analogue caused an initial increase in ventral prostatic weight after 4 days but suppressed the prostatic and testicular weights, the pituitary luteinizing hormone (LH) content, and plasma LH and testosterone levels after 10 and 17 days. All three antiandrogenic drugs used prevented the initial LHRH analogue-induced rise in prostatic weight, while RU 23908 suppressed its weight after only 4 days. After 10 and 17 days cyproterone acetate and RU 23908 had a similar significantly greater suppressive effect on prostatic and testicular weights than the LHRH analogue alone, while the additive inhibitory effect of ketoconazole was smaller. Surgical castration suppressed prostatic weight significantly more after 4 days, while its effects after 10 and 17 days were similar to that exerted by the combination of LHRH-A and RU 23908. The antigonadotropic effect of cyproterone acetate and the indirect gonadotropin-stimulating effects of ketoconazole and RU 23908 were not recognized in rats simultaneously treated with the LHRH analogue and did not interfere with the LHRH analogue-induced rapid depletion of the pituitary LH content and the decrease in circulating LH and testosterone levels. The LHRH analogue stimulated circulating progesterone and suppressed 17-hydroxyprogesterone levels. Ketoconazole and cyproterone acetate caused disorders in the pituitary-adrenal axis via different mechanisms: ketoconazole caused adrenal hypertrophy with normal circulating corticosterone levels caused by a compensatory increase in ACTH secretion; while cyproterone acetate exerted glucocorticoid-like effects causing a depletion of the pituitary adrenocorticotropic hormone content, adrenal atrophy, and lowered corticosterone levels. The addition of RU 23908 did not change the LHRH agonist-induced changes in adrenocortical activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Lamberts
S W
SW
Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
Uitterlinden
P
P
de Jong
F H
FH
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D002064:Buserelin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003534:Cyproterone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017373:Cyproterone Acetate; D003692:Delayed-Action Preparations; D017273:Goserelin; D007093:Imidazoles / Q000008:administration & dosage*; D048289:Imidazolidines; D007654:Ketoconazole / Q000008:administration & dosage*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D011919:Rats, Inbred Strains
D003692:Delayed-Action Preparations; D007093:Imidazoles; D048289:Imidazolidines; D017273:Goserelin; D017373:Cyproterone Acetate; C021277:nilutamide; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D003534:Cyproterone; D002064:Buserelin; D007654:Ketoconazole