LOW DOSES OF ANTI PROGESTIN ON EPITHELIAL PROLIFERATION IN ENDOMETRIUM

低剂量抗孕激素对子宫内膜上皮增殖的影响

• 批准号: 6247217
• 负责人: ROBERT M BRENNER
• 金额: $ 4.86万
• 依托单位: OREGON REGIONAL PRIMATE RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6247217
• 关键词: Mammalia; Primates; hormones; reproductive system; women's health

In macaques, progesterone stimulates epithelial cell proliferation in the endometrial basalis and inhibits estrogen-dependent epithelial proliferation in the endometrial functionalis. We have shown that antiprogestins inhibit estrogen-dependent growth of the primate endometrium. Here we report the effects of long-term treatment of intact cycling rhesus macaques with low doses of the potent antiprogestin ZK 137 316 (ZK ) on endometrial epithelial cell proliferation. Four groups of monkeys were injected daily for 5 cycles with 3 doses of ZK (none [vehicle], 0.01, 0.03 and 0.1 mg /kg body weight, i.m.). Uteri (n=3/ group) were collected on day 22 of the 5th cycle in the vehicle, 0.01 and 0.03 mg/kg groups, or 6-7 days after the estradiol peak in the 0.1 mg/kg group. Results of immuno-staining for Ki-67 antigen (% positive cells) and histological analysis of mitotic index (number of mitotic cells per 1000 epithelial cells) is shown in Table 1. Luteal phase P in vehicle treated controls inhibited cell proliferation in the endometrial functionalis (both Ki-67 staining and mitotic index) and stimulated proliferation in the basalis. ZK-treated animals showed a dose-dependent increase in the abundance of Ki-67-positive epithelial cells in the functionalis, and a dose dependent decrease in Ki-67 positive cells in basalis epithelium. This suggests that ZK inhibited P induced basalis proliferation, and by blocking P suppression of estrogen action, allowed estrogen to stimulate epithelial proliferation in the functionalis. However, at higher doses ZK appeared to also reduce the number of mitotic cells in the functionalis even though Ki-67 staining (an estrogen effect) was elevated. This suggests that ZK can block estrogen-stimulated cells in the functionalis from completing the cell cycle. These data further suggest that blockade of the cell cycle may contribute to inhibitory effects that antiprogestins have on endometrial development.

在猕猴中，孕酮刺激上皮细胞增殖 并抑制雌激素依赖性上皮细胞 功能性子宫内膜增生。 我们已经证明 抗孕激素抑制灵长类动物的雌激素依赖性生长 子宫内膜 在这里，我们报告的影响，长期治疗的 用低剂量的强效 ZK-137 - 316对子宫内膜上皮细胞的作用 增殖 四组猴子每天注射5次， 3个周期的ZK（无[溶媒]、0.01、0.03和0.1 mg /kg 体重，i.m.）。在试验的第22天收集子宫（n=3/组）。 溶剂、0.01和0.03 mg/kg组的第5个周期，或6-7天 0.1 mg/kg组雌二醇峰值后。 结果 Ki-67抗原的免疫染色（阳性细胞%）和组织学 有丝分裂指数（每1000个上皮细胞中有丝分裂细胞的数量）分析 细胞）的情况见表1。 溶媒处理的黄体期P 对照组抑制功能性子宫内膜细胞增殖 (both Ki-67染色和有丝分裂指数）和刺激增殖 在基底层 ZK治疗的动物显示出剂量依赖性增加 Ki-67阳性上皮细胞的丰度 功能性，Ki-67阳性细胞的剂量依赖性减少， 基底上皮 这表明ZK抑制P诱导的基底细胞凋亡， 增殖，并通过阻断P抑制雌激素作用， 使雌激素刺激上皮细胞增殖， functionalis. 然而，在较高剂量下，ZK似乎也减少了 尽管Ki-67染色，但功能区中有丝分裂细胞的数量 (an雌激素效应）升高。 这表明ZK可以阻断 雌激素刺激的细胞在functionalis完成细胞 周期 这些数据进一步表明，阻断细胞周期可能 有助于抑制抗孕激素对 子宫内膜发育