Gravanis A, Schaison G, George M, de Brux J, Satyaswaroop P G, Baulieu E E, Robel P
J Clin Endocrinol Metab. 1985 Jan;60(1):156-63. doi: 10.1210/jcem-60-1-156.
The effects of the antiprogestin RU 486 on the human endometrium were investigated. Seventeen postmenopausal women were injected with estradiol (E2) benzoate (0.625 mg/day) for 15 days. Progesterone (P) (25 mg/day) and/or RU 486 (100 or 200 mg/day) were given to groups of 2-3 women during the last 6 days of E2 benzoate treatment. Serial blood samples were drawn for the measurement of plasma E2, P, and LH and FSH. An endometrial biopsy was performed on the last day of treatment, and processed for histology or for assays of DNA polymerase alpha, E2-dehydrogenase (E2DH), and P receptor (PR). Treatment with E2 benzoate alone resulted in a marked decrease of plasma gonadotropins; in those patients who received either P, RU 486, or both, in addition to E2 benzoate, the concentrations of plasma LH and FSH were further decreased to premenopausal levels. In absence of glycerol, the affinity of RU 486 for the endometrial PR (Kd = 0.8 nM) was higher than that of P (Kd = 1.2 nM). Glycerol decreased markedly the affinity of RU 486, whereas the affinity of P for the PR was unchanged. RU 486 had negligible affinity for plasma transcortin. Either P or RU 486, but not both together, induced secretory changes in the endometrium as determined from histologic sections of tissue biopsies. Either P or RU 486 decreased DNA polymerase alpha and increased E2-DH activities in the endometrium. Unexpectedly, when P and RU 486 were given together. E2-DH activity remained at the level found in E2-treated women. In vitro cultures of proliferative endometrium treated with the synthetic progestagen R 5020 or with RU 486 also had increased E2-DH activity; RU 486 counteracted R 5020 effects. We conclude that, contrary to previous results with experimental animals, the anti-P RU 486 has some progestomimetic activity in humans under specific conditions. Paradoxically, when given together with P, RU 486 lost most of its progestomimetic activity in the endometrium and behaved as a pure antagonist.
研究了抗孕激素RU 486对人子宫内膜的影响。17名绝经后妇女每天注射苯甲酸雌二醇（E2）（0.625毫克），共15天。在苯甲酸雌二醇治疗的最后6天，给2 - 3名妇女组成的小组给予黄体酮（P）（每天25毫克）和/或RU 486（每天100或200毫克）。采集系列血样以测定血浆E2、P、促黄体生成素（LH）和促卵泡生成素（FSH）。在治疗的最后一天进行子宫内膜活检，并进行组织学处理或用于DNA聚合酶α、E2 - 脱氢酶（E2DH）和P受体（PR）的测定。单独用苯甲酸雌二醇治疗导致血浆促性腺激素显著降低；在那些除苯甲酸雌二醇外还接受P、RU 486或两者的患者中，血浆LH和FSH浓度进一步降至绝经前水平。在没有甘油的情况下，RU 486对子宫内膜PR的亲和力（解离常数Kd = 0.8纳摩尔）高于P（Kd = 1.2纳摩尔）。甘油显著降低了RU 486的亲和力，而P对PR的亲和力未变。RU 486对血浆皮质素转运蛋白的亲和力可忽略不计。从组织活检的组织学切片来看，单独给予P或RU 486均可诱导子宫内膜的分泌变化，但两者不能同时使用。单独给予P或RU 486均可降低子宫内膜中DNA聚合酶α的活性并增加E2 - DH的活性。出乎意料的是，当同时给予P和RU 486时，E2 - DH活性保持在接受E2治疗的妇女中所发现的水平。用合成孕激素R 5020或RU 486处理的增殖期子宫内膜的体外培养物中E2 - DH活性也有所增加；RU 486抵消了R 5020的作用。我们得出结论，与先前对实验动物的研究结果相反，抗P药物RU 486在特定条件下在人体中具有一些孕激素样活性。矛盾的是，当与P同时给予时，RU 486在子宫内膜中失去了其大部分孕激素样活性，表现为纯粹的拮抗剂。
