Halmos G, Schally A V, Pinski J, Vadillo-Buenfil M, Groot K
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Lousiana 70146, USA.
Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2398-402. doi: 10.1073/pnas.93.6.2398.
Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-R H (SB-75; Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 microg per rat. To determine whether the treatment with Cetrorelix can affect the concentration of measurable LH-RH binding sites, we applied an in vitro method to desaturate LH-RH receptors by chaotropic agents such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN). Our results show that the percentages of occupied LH-RH receptors at 1, 3, and 6 h after administration of Cetrorelix were approximately 28%, 14%, and 10%, respectively, of total receptors. At later time intervals, we could not detect occupied LH-RH binding sites. Ligand competition assays, following in vitro desaturation, demonstrated that rat pituitary LH-RH receptors were significantly (P < 0.01) down-regulated for at least 72 h after administration of Cetrorelix. The lowest receptor concentration was found 3-6 h after Cetrorelix treatment and a recovery in receptor number began within approximately 24 h. The down-regulation of LH-RH binding sites induced by Cetrorelix was accompanied by serum LH and testosterone suppression. Higher LH-RH receptor concentrations coincided with elevated serum hormone levels at later time intervals. Our results indicate that administration of LH-RH antagonist Cetrorelix produces a marked down-regulation of pituitary receptors for LH-RH and not merely an occupancy of binding sites.
促黄体生成激素释放激素（LH-RH）拮抗剂与LH-RH激动剂不同，给药后可立即抑制促性腺激素和性类固醇分泌，无初始刺激作用。[Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-RH（SB-75；西曲瑞克）是一种现代的、强效的LH-RH拮抗类似物。在本研究中，对每只大鼠单次注射100μg西曲瑞克后，研究了大鼠垂体前叶膜组分中LH-RH受体的结合特性。为了确定西曲瑞克治疗是否会影响可测量的LH-RH结合位点的浓度，我们应用体外方法，通过诸如氯化锰（MnCl2）和硫氰酸铵（NH4SCN）等离液剂使LH-RH受体去饱和。我们的结果显示，给药后1小时、3小时和6小时，被占据的LH-RH受体百分比分别约为总受体数的28%、14%和10%。在随后的时间间隔内，我们未检测到被占据的LH-RH结合位点。体外去饱和后的配体竞争试验表明，给药西曲瑞克后，大鼠垂体LH-RH受体至少在72小时内显著下调（P<0.01）。在西曲瑞克治疗后3 - 6小时发现受体浓度最低，且受体数量在约24小时内开始恢复。西曲瑞克诱导的LH-RH结合位点下调伴随着血清LH和睾酮抑制。在随后的时间间隔内，较高的LH-RH受体浓度与血清激素水平升高相一致。我们的结果表明，给予LH-RH拮抗剂西曲瑞克会导致垂体LH-RH受体显著下调，而不仅仅是结合位点的占据。
