新型抗孕激素ZK 98.299、ZK 98.734及RU 486对垂体促性腺细胞中促黄体生成素分泌及孕酮作用的调节作用

Modulatory actions of the new antiprogestins ZK 98.299 and ZK 98.734 and of RU 486 on luteinizing hormone secretion and progesterone effects in pituitary gonadotrophs.

作者信息

Ortmann O, Hansemann K, Knuppen R, Emons G

机构信息

Department of Obstetrics and Gynecology, Medical University of Lübeck, F.R.G.

出版信息

J Steroid Biochem. 1990 Aug 14;36(5):431-7. doi: 10.1016/0022-4731(90)90084-6.

DOI:10.1016/0022-4731(90)90084-6

PMID:2214762

Abstract

The effects of the antiprogestins (APs) ZK 98.299, ZK 98.734 and RU 486 on GnRH-stimulated LH secretion and their antagonistic activity on progesterone (P) actions were investigated in cultured pituitary cells from adult female Wistar rats. P (100 nM) was able to exert a facilitatory effect on GnRH (1 nM)-induced LH secretion after short-term (4 h) treatment of estradiol-primed (1 nM, 48 h) rat pituitary cells. When the APs (10 pM-10 microM) were introduced during the 4 h incubation period with P the facilitatory effect of P was totally abolished at concentrations greater than 10 nM (ZK 98.299, ZK 98.734) and greater than 1 nM (RU 486). Also the APs were shown to block the inhibitory action of P which occurs after long-term incubation of pituitary cells with this steroid. However at concentrations greater than 10 nM (ZK 98.734, RU 486) and greater than 100 nM (ZK 98.299) this antagonistic action of the APs was lost. To evaluate whether the APs have direct effects on GnRH-induced LH secretion in the absence of exogenous P pituitary cells cultivated for 48 h with or without 1 nM estradiol were incubated for 4 or 24 h with increasing concentrations of the APs (10 pM-10 microM). Four hour treatment of non-estradiol-primed cells with ZK 98.299 or ZK 98.734 was without any effect on the LH response to a 1 nM GnRH-stimulus. Only the highest concentration of RU 486 (10 microM) reduced the LH response. Twenty-four hour treatment of the cultures with the APs led to enhancement of GnRH-stimulated LH secretion by up to 113, 37 and 33% for ZK 98.734, ZK 98.299 and RU 486, respectively. When estradiol-primed cells were used for the same experiments we observed exclusively inhibitory effects on GnRH-induced LH secretion after 4 and 24 h treatment periods. It is concluded that these new APs are potent inhibitors of P-actions, but also per se they induce diverse effects on GnRH-stimulated LH secretion in cultured rat pituitary cells which have to be taken into account.

摘要

在成年雌性Wistar大鼠的培养垂体细胞中，研究了抗孕激素（APs）ZK 98.299、ZK 98.734和RU 486对促性腺激素释放激素（GnRH）刺激的促黄体生成素（LH）分泌的影响及其对孕酮（P）作用的拮抗活性。在用雌二醇预处理（1 nM，48小时）的大鼠垂体细胞短期（4小时）处理后，P（100 nM）能够对GnRH（1 nM）诱导的LH分泌发挥促进作用。当在与P孵育的4小时期间加入APs（10 pM - 10 microM）时，在浓度大于10 nM（ZK 98.299、ZK 98.734）和大于1 nM（RU 486）时，P的促进作用完全被消除。APs还显示出能阻断垂体细胞与这种类固醇长期孵育后P所产生的抑制作用。然而，在浓度大于10 nM（ZK 98.734、RU 486）和大于100 nM（ZK 98.299）时，APs的这种拮抗作用消失。为了评估在没有外源性P的情况下APs是否对GnRH诱导的LH分泌有直接影响，将在有或没有1 nM雌二醇的情况下培养48小时的垂体细胞与浓度不断增加的APs（10 pM - 10 microM）孵育4小时或24小时。用ZK 98.299或ZK 98.734对未用雌二醇预处理的细胞进行4小时处理，对LH对1 nM GnRH刺激的反应没有任何影响。只有最高浓度的RU 486（10 microM）降低了LH反应。用APs对培养物进行24小时处理导致ZK 98.734、ZK 98.299和RU 486分别使GnRH刺激的LH分泌增强高达113%、37%和33%。当使用经雌二醇预处理的细胞进行相同实验时，在4小时和24小时处理期后，我们仅观察到对GnRH诱导的LH分泌有抑制作用。得出的结论是，这些新的APs是P作用的有效抑制剂，但它们本身也会对培养的大鼠垂体细胞中GnRH刺激的LH分泌产生不同影响，这一点必须予以考虑。