Effect of 3-week treatment with [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination on testicular, serum, adrenal and prostatic steroid levels in the dog.
Adult male mongrel dogs were treated with the LHRH agonist [D-Trp6, des-Gly-NH10(2)]LHRH ethylamide, aminoglutethimide, ketoconazole or flutamide alone or in combination for 21 days before measurement of steroid levels in the testes, prostate, adrenals and serum. Ketoconazole alone caused a marked stimulation of the intra-testicular concentration of pregnenolone, 17OH-pregnenolone, progesterone and 17OH-progesterone with no or little change of androstenedione, testosterone and dihydrotestosterone. Aminoglutethimide caused a 30-95% inhibition in the concentration of all steroids in the tests while treatment with the LHRH agonist caused a near complete inhibition of all testicular steroids. When administered concomitantly with the LHRH agonist, ketoconazole partly prevented the inhibitory effect of the LHRH agonist on testicular steroid levels. Serum levels of dehydroepiandrosterone, androst-5-ene-3 beta,17 beta-diol, androstenedione and androstane-3 alpha, 17 beta-diol were 75 to 95% inhibited by the LHRH agonist while serum testosterone and dihydrotestosterone concentrations were reduced below detection limits by the same treatment. Moreover, treatment with the LHRH agonist caused a 70-95% reduction in the intraprostatic concentration of testosterone and dihydrotestosterone in all the groups although maximal effect was observed when the LHRH agonist was combined with any of the three other agents. The present data show that while treatment with ketoconazole, aminoglutethimide or Flutamide alone has only partial inhibitory effects on androgen levels, combination with an LHRH agonist provides maximal inhibition. In addition to its direct blockade of the androgen receptor, some of the effect of Flutamide could be related to its blockade of testicular 3 beta-hydroxy-steroid dehydrogenase activity.
Lacoste
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D
MRC Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Caron
S
S
Bélanger
A
A
Labrie
F
F
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000616:Aminoglutethimide / Q000494:pharmacology; D000728:Androgens / Q000097:blood / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D005485:Flutamide / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D013737:Testis / Q000187:drug effects / Q000378:metabolism*; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives*
D000728:Androgens; D017329:Triptorelin Pamoate; D000616:Aminoglutethimide; D007987:Gonadotropin-Releasing Hormone; C019176:Tryptal; D005485:Flutamide; D007654:Ketoconazole