The rise in testicular androgens during the first days of treatment with an LHRH agonist in the dog can be blocked by aminoglutethimide or ketoconazole.
Up to day 6 of treatment of adult dogs, daily subcutaneous administration of 50 micrograms of the LHRH agonist [D-Trp6, des-Gly-NH2-10]LHRH ethylamide causes up to a 3-fold increase in serum testosterone (T) concentration which is followed by a progressive decrease to castration levels (less than or equal to 0.2 ng/ml) at later time intervals (up to 21 days, the last time interval studied). Both aminoglutethimide and ketoconazole, two inhibitors of steroid biosynthesis, cause a 30-40% rise in serum T when administered alone. However, either drug administered in combination with the LHRH agonist completely blocks the transient rise in serum T observed when the LHRH agonist is administered alone. On the other hand, the LHRH agonist prevents the secondary rise in steroid secretion observed when either of the two inhibitors of steroid secretion is used alone. Administration of the pure antiandrogen Flutamide alone or in combination with LHRH-A and an inhibitor of steroid biosynthesis does not influence serum T levels. When the serum levels of pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone, dehydroepiandrosterone (DHEA), androstenedione (delta 4-dione), androst-5-ene-3 beta, 17 beta-diol (delta 5-diol), T, dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol, androstane-3 beta. 17 beta-diol and 17 beta-estradiol (E2) are analyzed in detail, it can be seen that both aminoglutethimide and ketoconazole not only prevent the rise in serum steroids observed during the first 8 days of treatment with the LHRH agonist but that both compounds enhance the inhibitory effect of the LHRH agonist at later time intervals. A predominant inhibitory effect of ketoconazole is exerted on 17,20-desmolase activity. Aminoglutethimide has little influence on the loss of serum LH bioactivity induced by the LHRH agonist while ketoconazole stimulates the concentration of serum bioactive LH in the absence or presence of simultaneous treatment with the LHRH agonist. The present data clearly demonstrate that aminoglutethimide or ketoconazole can prevent the rise in serum androgens accompanying the first days of treatment with an LHRH agonist in the dog. Moreover, after 3 weeks of treatment, the inhibitory effect of the LHRH agonist on serum androgen levels is enhanced by addition of aminoglutethimide or ketoconazole. Moreover, Flutamide does not interfere with the inhibitory action of the LHRH agonist, aminoglutethimide or ketoconazole, thus suggesting that maximal inhibition of androgen action is likely to be achieved by a combination of these drugs.
Lacoste
D
D
Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
St-Arnaud
R
R
Caron
S
S
Belanger
A
A
Labrie
F
F
D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors; D000616:Aminoglutethimide / Q000494:pharmacology*; D000728:Androgens / Q000097:blood*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004958:Estradiol / Q000097:blood; D005485:Flutamide / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D011284:Pregnenolone / Q000097:blood; D011374:Progesterone / Q000097:blood; D013254:Steroid 17-alpha-Hydroxylase; D013737:Testis / Q000187:drug effects*; D013739:Testosterone / Q000097:blood; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives*
D000728:Androgens; D065607:Cytochrome P-450 Enzyme Inhibitors; D017329:Triptorelin Pamoate; D000616:Aminoglutethimide; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; C019176:Tryptal; D011284:Pregnenolone; D005485:Flutamide; D007986:Luteinizing Hormone; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D007654:Ketoconazole