Blockade of the LH response induced by the agonist D‐Trp‐6‐LHRH in rats by a highly potent LH‐RH antagonist SB‐75

Abstract

During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 micrograms/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50 micrograms/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 micrograms/rat 3 days prior to administration of the agonist significantly lowered LH response (P less than 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 micrograms/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 micrograms/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 micrograms/rat) on LH secretion could be totally suppressed by an injection of 50 micrograms/rat of SB-75 1 hour beforehand.(ABSTRACT TRUNCATED AT 400 WORDS)

GnRH Antagonist-induced Down-regulation of the mRNA Expression of Pituitary Receptors: Comparisons with GnRH Agonist Effects

“…The apparently opposing impact of GnRHant on GnRHa-induced down-regulation of pituitary receptors raises interesting questions regarding the potential effects of concurrent administration. Regarding the impact of GnRHant on the GnRHa-induced flare-up phenomenon, GnRHant partially inhibited the initial flare-up caused by GnRHa treatment in this study, and Pinski et al [15] described that pretreatment with GnRHant (500 or 1000 mg/rat) 1 hour before GnRHa (50 mg/rat) in male rats could completely prevent the elevation of LH. However, GnRHant did not diminish GnRHa-induced gonadotropin desensitization during prolonged treatment in the present study.…”

Maximal androgen withdrawal for prostate cancer therapy: current status and future potential

“…Experimental data were conducted using LHRH antagonists which directly block the LHRH receptor and result in immediate suppression of androgen production (Pinski et al 1992). Unfortunately, early results were associated with histamine releasing anaphylactoid reaction, relative water insolubility, and the necessity of using acidic formulation for delivery (Garnick 1997).…”

Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist Cetrorelix with growth inhibition

“…These experimental results suggest a regulatory role for LHRH-like peptides on tumor growth (14,18,21,27,28). Consequently LHRH antagonists like Cetrorelix could be considered for the development of new therapies for LHRH receptor positive cancers (17).…”