Potent synthetic analogs of gonadotropin-releasing hormone produce paradoxical anti-reproductive effects when administered chronically. These compounds are minimally toxic and may exhibit no plateau of the dose-response curve even at very high doses. These considerations served as the basis for our systematic evaluation of [D-leucine6-desarginine-glycine-NH210]gonadotropin-releasing hormone (GnRH-A) proethylamide in the very high dose range (i.e., 10-fold larger amounts than previously used). In rats given the analog for 12 wk, prostate, testis, and seminal vesicle weights were suppressed to a greater extent with 200 μg q.d. than with 40 μg q.d. (P < 0.01 prostate, < 0.01 testis, < 0.01 seminal vesicles), indicating dose-response effects in the very high dose range. 200 μg of [D-Leu6-des-Gly-NH210]-GnRH-A consistently suppressed luteinizing hormone (LH) values at 6 and 12 wk (basal 71 ± 9.5; 6 wk 34 ± 3.8; 12 wk 28 ± 5 ng/ml) whereas 40 μg suppressed LH variably (basal 33 ± 3.8; 6 wk 17 ± 3.9; 12 wk 32 ± 5.2). Testosterone fell to 15 ± 2.4 and 19 ± 2.0 ng/100 ml in response to 200 μg q.d. and to 27 ± 6.4 and 22 ± 7.4 ng/100 ml with the 40-μg dose. These findings in the rodent prompted treatment of stage D prostate cancer patients with similarly high doses of [D-Leu6-des-Gly-NH210]-GnRH-A. After treatment for 11 wk with 1,000 or 10,000 μg/d of the analog, testosterone and dihydrotestosterone levels transiently rose and then fell into the surgically castrate range (testosterone 19 ± 4.4 ng/100 ml [D-Leu6-des-Gly-NH210]-GnRH-A vs. surgically castrate 11 ± 0.9 ng/100 ml, P = NS; dihydrotestosterone 15 ± 1.7 ng/100 ml GnRH-A vs. surgically castrate 15 ± 4.4 ng/100 ml, P = NS). However, unlike the chronic stimulatory effect on the pituitary at lower doses, very high dose therapy resulted in profound suppression of plasma and urine LH. Plasma levels fell to the limit of assay detectability, whereas the more sensitive urinary assay detected prepubertal levels of excretion (i.e., 64 ± 8.4 mIU/h). The highly sensitive rat interstitial cell testosterone bioassay for LH also demonstrated a marked decline in LH to undetectable levels in 17/19 subjects. Clinical results with [D-Leu6-des-Gly-NH210]-GnRH-A simulate those achieved by surgical castration in men with prostatic cancer as suggested by available preliminary data.
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