Suppression of pituitary-gonadal function by a potent new luteinizing hormone-releasing hormone antagonist in normal men.
Suppression of pituitary-gonadal function by a potent new luteinizing hormone-releasing hormone antagonist in normal men.
复制标题
一种有效的新型黄体生成素释放激素拮抗剂对正常男性的垂体性腺功能的抑制。
DOI：
10.1210/jcem-64-5-931
复制
发表时间：
1987
期刊：
影响因子：
--
通讯作者：
W. Kovacs
中科院分区：
文献类型：
--
作者：
S. Pavlou;G. Wakefield;D. Island;P. Hoffman;M. Lepage;R. Chan;C. Nerenberg;W. Kovacs
LHRH拮抗剂与内源性LHRH竞争结合垂体促性腺激素细胞上的受体，从而通过抑制促性腺激素分泌来抑制性腺功能。本文研究了新近研制的LHRH拮抗剂地替瑞克[（N-Ac-D-Nal（2）1，D-pCl-Phe 2，D-Trp 3，D-hArg（Et 2）6，D-Ala 10]LHRH]对人垂体-性腺轴的影响。在治疗前、拮抗剂给药后48 h和72、96和168 h频繁测量血清FSH、LH和睾酮水平。5、10和20 mg给药后，平均血清FSH水平分别从6.9 +/- 0.5（+/- SEM）mIU/mL降至最低值4.4 +/- 1.1、3.6 +/- 0.9和4.1 +/- 0.9（P <0.001）。三次给药后，血清LH水平从6.2 +/- 0.3 mIU/mL降至最低值3.3 +/- 0.4、2.8 +/- 0.3和2.7 +/- 0.3（P <0.001）。血清睾酮水平以剂量依赖性方式从5.1 +/- 0.2 ng/mL降至相同剂量后的最低值1.3 +/- 0.3、0.9 +/- 0.3和0.6 +/- 0.1（P <0.001）。然而，在最初的睾酮减少后，逃逸发生在较低剂量后12-28小时。反应曲线下面积描述了研究期间激素浓度随时间的变化，FSH减少23 +/-2%、36 +/-4%和36 +/- 3%，LH减少14 +/-6%、30% +/-6%和34 +/- 5%，LH减少41 +/-5%、58 +/-6%，相同剂量的睾酮分别为68 +/- 4%。在所有三次给药后，通过RIA测定的地替瑞克的表观血浆消失半衰期至少为41小时。地替瑞克仅引起轻微的局部反应;在所用剂量范围内未观察到全身副作用。这些结果表明，这种LHRH拮抗剂是一种安全、高效的人垂体-性腺轴抑制剂，具有非常长的作用持续时间。
LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadal function by suppressing gonadotropin secretion. We studied the effects of a recently developed LHRH antagonist on the pituitary-gonadal axis in man. The antagonist Detirelix [( N-Ac-D-Nal(2)1, D-pCl-Phe2,D-Trp3, D-hArg(Et2)6, D-Ala10]LHRH) was given as a single sc injection to nine normal men at three dose levels (5, 10, and 20 mg) at intervals of at least 7 days. Serum FSH, LH, and testosterone levels were measured before treatment, at frequent intervals for 48 h, and 72, 96, and 168 h after administration of the antagonist. Mean serum FSH levels decreased (P less than 0.001) from 6.9 +/- 0.5 (+/- SEM) mIU/mL to nadirs of 4.4 +/- 1.1, 3.6 +/- 0.9, and 4.1 +/- 0.9 after the 5-, 10-, and 20-mg doses, respectively. Serum LH levels decreased (P less than 0.001) from 6.2 +/- 0.3 mIU/mL to nadirs of 3.3 +/- 0.4, 2.8 +/- 0.3, and 2.7 +/- 0.3 after all three doses. Serum testosterone levels decreased (P less than 0.001) in a dose-dependent fashion from 5.1 +/- 0.2 ng/mL to nadirs of 1.3 +/- 0.3, 0.9 +/- 0.3, and 0.6 +/- 0.1 after the same doses. After the initial testosterone decrease, however, escape occurred 12-28 h after the lower doses. The area under the response curve, describing hormone concentrations as a function of time during the study, diminished by 23 +/- 2%, 36 +/- 4%, and 36 +/- 3% for FSH, by 14 +/- 6%, 30% +/- 6%, and 34 +/- 5% for LH, and by 41 +/- 5%, 58 +/- 6%, and 68 +/- 4% for testosterone with the same doses, respectively. The apparent plasma disappearance half-life of Detirelix by RIA was at least 41 h after all three doses. Detirelix elicited only a minor local reaction; no systemic side-effects were observed within the dose range used. These results indicate that this LHRH antagonist is a safe, highly potent inhibitor of the human pituitary-gonadal axis with an exceptionally long duration of action.