Stormshak F, Leake R, Wertz N, Gorski J
Endocrinology. 1976 Dec;99(6):1501-11. doi: 10.1210/endo-99-6-1501.
The induction of long-term responses in the uterus following estrogen treatment is discussed, with special reference to DNA synthesis. Immature female rats injected daily with estradiol-17beta or estriol (0.01 to 1 mug) or a combination of the two steroids for one, two or three consecutive days were sacrificed at intervals from 12 to 24 h after the last injection of vehicle or steroid. In vitro incorporation of [3H]thymidine into DNA [14C]leucine into protein, and oxidation of [14C)glucose to 14CO2 were determined. Nuclear-bound estradiol was determined by use of exchange assay or following incubation of intact uteri with 1 X 10(-8)M ([3H]estradiol for 1 h at 37 C. Injection of estriol only partially stimulated DNA synthesis by 18 to 24 h post-treatment. However, injection of estriol followed by injection of estradiol 6 h later resulted in increased DNA synthesis, suggesting that estrogen must be present for up to 6 h to induce subsequent DNA synthesis. Maximal DNA and protein synthesis and oxidation of glucose occurred at 24 h after injection of estradiol (0.1 or 1 mug) but was depressed to control levels by 24 h after the last of three daily injections. Daily injections of 0.01 mug of estradiol resulted in a similar pattern of DNA synthesis, although of lesser magnitude than that observed after injection of 0.1 or 1 mug of estradiol. However, if rats receiving daily injections of 0.01 mug estradiol were challenged with a higher dose of estradiol (1 mug), uterine DNA synthesis was markedly increased. The data suggest that prolonged exposure to estrogen causes uterine cells to become metabolically "refractory" to further estrogen stimulation. Sequential injections of estriol (1 mug) or intermittent injections of estradiol (1 mug) were ineffective in causing this uterine "refractoriness". Receptor binding of estrogen, translocation to the nucleus, and retention of receptor in the nucleus were not affected by sequential estrogen treatment. The accumulation of an inhibitory product is suggested as a possible explanation for this phenomenon.
本文讨论了雌激素治疗后子宫内长期反应的诱导，特别提及了DNA合成。将未成熟雌性大鼠每日注射雌二醇-17β或雌三醇（0.01至1微克）或两种类固醇的组合，连续注射1、2或3天，在最后一次注射赋形剂或类固醇后的12至24小时内间隔处死。测定了[3H]胸腺嘧啶核苷在体外掺入DNA、[14C]亮氨酸掺入蛋白质以及[14C]葡萄糖氧化为14CO2的情况。通过交换测定法或完整子宫在37℃下与1×10(-8)M（[3H]雌二醇）孵育1小时后测定核结合雌二醇。仅注射雌三醇在治疗后18至24小时仅部分刺激DNA合成。然而，先注射雌三醇，6小时后再注射雌二醇，会导致DNA合成增加，这表明雌激素必须存在长达6小时才能诱导随后的DNA合成。注射雌二醇（0.1或1微克）后24小时出现最大的DNA和蛋白质合成以及葡萄糖氧化，但在连续三天每日注射中的最后一次注射后24小时降至对照水平。每日注射0.01微克雌二醇导致类似的DNA合成模式，尽管幅度小于注射0.1或1微克雌二醇后观察到的幅度。然而，如果每日注射0.01微克雌二醇的大鼠用更高剂量的雌二醇（1微克）进行刺激，子宫DNA合成会显著增加。数据表明，长期暴露于雌激素会使子宫细胞在代谢上对进一步的雌激素刺激变得“不应答”。连续注射雌三醇（1微克）或间歇注射雌二醇（1微克）在导致这种子宫“不应答”方面无效。雌激素的受体结合、向细胞核的转位以及受体在细胞核中的保留不受连续雌激素治疗的影响。有人提出一种抑制性产物的积累可能是对此现象的一种解释。
