Trivedi R N, Chauhan S C, Dwivedi A, Kamboj V P, Singh M M
Central Drug Research Institute, Lucknow, India.
Contraception. 1995 Jun;51(6):367-79. doi: 10.1016/0010-7824(95)00103-h.
Time-related estrogen antagonistic action of a single oral contraceptive (1.25 mg/kg) dose of the triphenylethylene antiestrogen centchroman was determined in ovariectomized immature rats. Tamoxifen and nafoxidine were used for comparison. A single oral administration of centchroman followed by three doses of estradiol-17 beta (1 microgram/d, s.c.) caused significant dose-dependent inhibition in estradiol-17 beta-induced increase in uterine weight and nuclear and cytosolic estrogen receptors. But the inhibition at antiimplantation dose was evident only if estradiol-17 beta treatment was initiated not later than 48 h post-antiestrogen. Alternatively, when antiestrogen treatment was followed by a single dose of estradiol-17 beta between days 2-7, a synergistic action, typical of antiestrogens possessing weak estrogen agonistic activity, was observed. In immature rats in which a condition mimicking preimplantation was produced by estradiol-17 beta (0.5 microgram/d, s.c.) priming on days -2 and -1, followed by progesterone (1 mg/d, s.c.) and an endometrial sensitizing dose (0.5 microgram/d, s.c.) of estradiol-17 beta at 1600 h on day 4, anti-implantation dose of centchroman administered on day 1, too, failed to inhibit uterine weight gain induced by sensitizing dose of estradiol-17 beta, but caused marked inhibition in endometrial sensitivity to a deciduogenic stimulus and decidualization and weight gain of traumatized uterine horn 96 h post-traumatization over non-traumatized horn was only about 150% (725% in controls). Inhibition in endometrial sensitivity and decidualization was evident when the interval between antiestrogen treatment and sensitizing estradiol was < 126 h. Pinopods were present on endometrial surface on day 5 whether or not priming and/or sensitizing doses of estradiol were administered, but decidual response was mild if either of these doses of estradiol-17 beta was deferred. Findings suggest that: (a) duration of antiestrogenic action of single anti-implantation dose of centchroman in rat was about 126 h, which in ovariectomized immature rats was evident only when a condition mimicking preimplantation was produced and the antiestrogenic response was based on inhibition in estradiol-induced endometrial sensitivity and not uterine weight gain; (b) priming as well as sensitizing estrogen were essential to get optimal decidual responses; (c) appearance of pinopods on endometrial surface may not be related to endometrial sensitivity; and (d) tamoxifen and nafoxidine appear slightly longer acting with duration of antiestrogenic action of approximately 150 h.
在去卵巢的未成熟大鼠中测定了单次口服避孕药剂量（1.25毫克/千克）的三苯乙烯类抗雌激素药物左旋炔诺孕酮的时间相关雌激素拮抗作用。使用他莫昔芬和奈法唑酮作为对照。单次口服左旋炔诺孕酮后再给予三剂雌二醇-17β（1微克/天，皮下注射），可导致雌二醇-17β诱导的子宫重量以及核和胞质雌激素受体增加出现显著的剂量依赖性抑制。但仅当在抗雌激素给药后不迟于48小时开始进行雌二醇-17β治疗时，抗着床剂量的抑制作用才明显。另外，当抗雌激素治疗后在第2至7天给予一剂雌二醇-17β时，观察到了具有弱雌激素激动活性的抗雌激素典型的协同作用。在通过在第-2天和第-1天皮下注射雌二醇-17β（0.5微克/天）进行预处理，随后在第4天皮下注射孕酮（1毫克/天）以及在1600时皮下注射一剂子宫内膜致敏剂量（0.5微克/天）的雌二醇-17β而模拟着床前状态的未成熟大鼠中，在第1天给予抗着床剂量的左旋炔诺孕酮也未能抑制致敏剂量的雌二醇-17β诱导的子宫重量增加，但导致子宫内膜对蜕膜化刺激的敏感性以及蜕膜化和创伤后96小时创伤子宫角重量增加相对于未创伤子宫角仅约为150%（对照组为725%）出现显著抑制。当抗雌激素治疗与致敏雌二醇之间的间隔<126小时时，子宫内膜敏感性和蜕膜化的抑制作用明显。无论是否给予雌二醇的预处理和/或致敏剂量，在第5天子宫内膜表面均存在胞饮突，但如果推迟这两种剂量的雌二醇-17β中的任何一种，则蜕膜反应较轻。研究结果表明：（a）单次抗着床剂量的左旋炔诺孕酮在大鼠中的抗雌激素作用持续时间约为126小时，在去卵巢的未成熟大鼠中，仅当模拟着床前状态且抗雌激素反应基于对雌二醇诱导的子宫内膜敏感性而非子宫重量增加的抑制时才明显；（b）预处理和致敏雌激素对于获得最佳蜕膜反应均必不可少；（c）子宫内膜表面胞饮突的出现可能与子宫内膜敏感性无关；（d）他莫昔芬和奈法唑酮的作用时间似乎稍长，抗雌激素作用持续时间约为150小时。
