1. 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
D Lacoste, S Caron, A Bélanger, F Labrie J Steroid Biochem. 1989 Aug;33(2):233-42. doi: 10.1016/0022-4731(89)90299-9.
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.
2. Effect of 2-week combination therapy with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide and the antiandrogen flutamide on prostate structure and steroid levels in the dog
D Lacoste, D Dubé, A Bélanger, F Labrie Mol Cell Endocrinol. 1989 Dec;67(2-3):131-8. doi: 10.1016/0303-7207(89)90202-5.
Treatment of adult dogs for 15 days with the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (50 micrograms daily, s.c.) causes a 41.6% inhibition of prostatic weight while a 55% inhibition is achieved when the antiandrogen flutamide (250 mg, twice daily) is given in association with the LHRH agonist (p less than 0.01). At histology, the glandular acini in the prostate of animals treated with the combination therapy are more atrophied than with either treatment used alone. A 2-week treatment with the LHRH agonist is characterized by two distinct phases, namely a stimulation of testicular androgen secretion between days 0 and 8 followed by an inhibition between days 9 and 15. During the inhibitory phase, the concentration of all testicular steroids progressively decreased to castration levels, thus indicating that the differences observed at the prostatic level at 2 weeks are due to the inhibition of androgen action by the antiandrogen flutamide during the period which precedes complete chemical castration by the LHRH agonist. Flutamide administered alone had no effect on plasma or prostatic steroid levels measured after 2 weeks and it did not interfere with the potent and generalized inhibitory effect of the LHRH agonist on the serum and prostatic concentration of all steroids measured.(ABSTRACT TRUNCATED AT 250 WORDS)
3. Biopharmaceutic stability of [D-Trp6, des-Gly10]-LHRH ethyl amide in corn oil
R H Naqvi, M C Lindberg Endocr Res. 1985;11(3-4):139-44. doi: 10.1080/07435808509032972.
When sperm-positive female rats were treated with freshly prepared formulations of [D-Trp6, des-Gly10]-LHRH ethyl amide (LRA) in corn oil, the effects on pregnancy occurred in a dose-related manner. When the same formulation was retested after five-and-a-half years of storage under refrigeration, the results were essentially identical. Therefore, the biopharmaceutic stability of corn oil formulations of LRA appears to be 100% following five-and-a-half years of storage at 4 degrees C.
