Srivastava R K, Sridaran R
Department of Physiology, Morehouse School of Medicine, Atlanta, GA 30310-1495.
Endocr Res. 1994 Nov;20(4):365-76. doi: 10.1080/07435809409030412.
We have examined the effect of two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) on the basal progesterone (P4), pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained from day 8 pregnant rats. A dose of 0.1 mmol/l of Nal-Glu or Nal-Arg attenuated basal P4 production by luteal cells after 12, 24 or 48 h of incubation. P5, a precursor for P4 synthesis was also reduced by both doses of Nal-Glu or Nal-Arg (0.1 mmol or 0.1 mumol/l) after 24 h of incubation. A period of 12 h was not sufficient to inhibit P5 production by luteal cells incubated with both doses of Nal-Glu or with the lower dose of Nal-Arg. The higher dose of Nal-Glu and Nal-Arg remained effective in attenuating P5 production by luteal cells after 48 h of incubation. We measured the production of a metabolite of P4, i.e., 20 alpha-DHP to assess whether this suppression in P4 production is due to an enhancement in the P4 metabolism by increasing the activity of 20 alpha-hydroxydehydrogenase. However, instead, we observed (i) a decrease in the production of 20 alpha-DHP by the higher dose of Nal-Glu and Nal-Arg after 12, 24 or 48 h of incubation and (ii) a decrease or no change in the production of 20 alpha-DHP by the lower dose of Nal-Glu or Nal-Arg at all time periods of incubation. Based on these observations we conclude that LHRH antagonists exert a direct effect on the corpus luteum and suppress luteal steroidogenesis. This suppression in luteal steroidogenesis could be due to a decrease in the activity of any one of these enzymes of the steroidogenic pathway, viz., cholesterol side chain cleavage (P450scc), a rate limiting enzyme involved in the synthesis of P5 from cholesterol, or 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which catalyzes the oxidation of P5 to P4 or due to a decrease in activity of both enzymes.
我们研究了两种促黄体生成素释放激素（LHRH）拮抗剂（Nal-Glu和Nal-Arg拮抗剂）对从妊娠第8天大鼠获取的黄体细胞基础孕酮（P4）、孕烯醇酮（P5）和20α-二氢孕酮（20α-DHP）分泌的影响。在孵育12、24或48小时后，0.1 mmol/l的Nal-Glu或Nal-Arg剂量可减弱黄体细胞基础P4的分泌。P5是P4合成的前体，在孵育24小时后，两种剂量的Nal-Glu或Nal-Arg（0.1 mmol或0.1 μmol/l）也使其减少。12小时的时间不足以抑制与两种剂量的Nal-Glu或较低剂量的Nal-Arg一起孵育的黄体细胞的P5分泌。在孵育48小时后，较高剂量的Nal-Glu和Nal-Arg在减弱黄体细胞P5分泌方面仍然有效。我们测量了P4的一种代谢产物即20α-DHP的分泌，以评估P4分泌的这种抑制是否是由于通过增加20α-羟基脱氢酶的活性而增强了P4代谢所致。然而，相反地，我们观察到：（i）在孵育12、24或48小时后，较高剂量的Nal-Glu和Nal-Arg使20α-DHP的分泌减少；（ii）在所有孵育时间段内，较低剂量的Nal-Glu或Nal-Arg使20α-DHP的分泌减少或无变化。基于这些观察结果，我们得出结论，LHRH拮抗剂对黄体发挥直接作用并抑制黄体类固醇生成。黄体类固醇生成的这种抑制可能是由于类固醇生成途径中的任何一种酶的活性降低，即胆固醇侧链裂解酶（P450scc），一种参与从胆固醇合成P5的限速酶，或3β-羟基类固醇脱氢酶（3β-HSD），它催化P5氧化为P4，或者是由于这两种酶活性均降低。
