Donath J, Michna H, Nishino Y
Research Laboratories of Schering AG, Berlin, Germany.
J Steroid Biochem Mol Biol. 1997 May;62(1):107-18. doi: 10.1016/s0960-0760(97)00012-5.
The present study was undertaken to investigate intraovarian mechanism(s) for the antiovulatory effect of Onapristone (ON), because antiprogestins possessing the same antiprogestational activity and inhibiting the preovulatory LH surge to the same extent differ in their antiovulatory potency. Ovulation was induced by treating immature female rats with pregnant mare serum gonadotropin (PMSG) for folliculogenesis and hCG for the induction of ovulation. The animals were treated twice with ON (200 mg/kg 42 h and 48 h after PMSG) and killed at different times. The ovulation rate was assessed by counting the number of ova in the fallopian tubes and uteri. Blood and ovaries were collected for radioimmunoassay (RIA) of steroid hormones and histological analysis for 3beta-hydroxysteroid dehydrogenase (3beta-HSDH), 17beta-hydroxysteroid dehydrogenase (17beta-HSDH), progesterone (PR), estrogen (ER) and androgen (AR) receptors. Treatment with ON totally blocked ovulation and the progesterone (P4) surge was significantly diminished in comparison to the control (6-8 h post-hCG), whereas androgen levels remained unaffected. The decreased P4 concentrations correlated well with a reduced staining intensity of 3beta-HSDH in granulosa cells of tertiary follicles. Moreover, we observed a down-regulation of PR in granulosa cells of tertiary follicles. Additionally, in secondary and tertiary follicles the expression of AR between 0 and 6 h after hCG was reduced. These results suggest that the antiovulatory effect of the antiprogestin ON is related to down-regulation of intraovarian progesterone, caused by attenuated 3beta-HSDH activity and PR expression. One can thus assume that intraovarian P4 is an important factor for the induction of ovulation. An effect of ON on the staining intensity of 17beta-HSDH in theca and granulosa cells could not be observed at any time. In conclusion, the inhibition of ovulation induced by the antiprogestin, ON, could be related to decreased intraovarian progesterone production through reduced 3beta-HSDH activity and the down-regulation of PR.
本研究旨在探讨孕三烯酮（ON）抗排卵作用的卵巢内机制，因为具有相同抗孕激素活性且同等程度抑制排卵前促黄体生成素高峰的抗孕激素，其抗排卵效力存在差异。通过给未成熟雌性大鼠注射孕马血清促性腺激素（PMSG）以促进卵泡生成，再注射人绒毛膜促性腺激素（hCG）以诱导排卵。动物在注射PMSG后42小时和48小时分两次给予ON（200mg/kg），并在不同时间处死。通过计数输卵管和子宫内的卵子数量评估排卵率。采集血液和卵巢用于甾体激素的放射免疫测定（RIA）以及对3β-羟基类固醇脱氢酶（3β-HSDH）、17β-羟基类固醇脱氢酶（17β-HSDH）、孕激素受体（PR）、雌激素受体（ER）和雄激素受体（AR）进行组织学分析。与对照组（hCG后6 - 8小时）相比，ON处理完全阻断了排卵，且孕激素（P4）高峰显著降低，而雄激素水平未受影响。P4浓度降低与三级卵泡颗粒细胞中3β-HSDH染色强度降低密切相关。此外，我们观察到三级卵泡颗粒细胞中PR下调。另外，在二级和三级卵泡中，hCG后0至6小时AR的表达降低。这些结果表明，抗孕激素ON的抗排卵作用与卵巢内孕激素下调有关，这是由3β-HSDH活性和PR表达减弱所致。因此可以推测，卵巢内P4是诱导排卵的重要因素。在任何时候均未观察到ON对卵泡膜和颗粒细胞中17β-HSDH染色强度的影响。总之，抗孕激素ON诱导的排卵抑制可能与通过降低3β-HSDH活性和PR下调导致的卵巢内孕激素生成减少有关。
