Vårdvetenskapligt Forskningscentrum/Centre for Health Sciences, Örebro University Hospital, County Council of Örebro, Örebro SE-703 62, Sweden.
BMC Neurosci. 2014 Feb 4;15:22. doi: 10.1186/1471-2202-15-22.
Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for.
The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats.
We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.
尽管大多数动物中风研究都表明雌激素具有强大的神经保护作用，但也有许多文章报告了相反的结果。2009 年，我们提出这种二分法与给予的雌激素剂量有关。对于不一致的结果，也提出了其他一些建议，包括实验动物的年龄和给予雌激素前低雌激素血症的持续时间。这两个建议得到了广泛的关注，可能是因为它们与机会窗口假说有关，该假说常用于解释人类研究中的类似二分法。因此，我们鼓励进行更新的荟萃分析，并通过在一个大型多元回归模型中包含所有相关变量来改进它，从而可以控制混杂因素的影响。
多元回归模型显示，雌激素给药方式对缺血性中风中雌激素的作用有不可争议的影响。皮下缓释微球与注射和硅橡胶囊治疗在雌激素对缺血性中风的影响方面存在差异，表明前者更容易使雌激素产生损伤作用。使用老年动物或采用更长的洗脱期均不会影响雌激素对大鼠实验性缺血性中风的作用。
我们得出结论，关于雌激素在大鼠缺血性中风模型中的作用的不一致结果是雌激素给药方式不同的结果。这些结果不仅对正在进行的关于绝经激素治疗的争论很重要，而且对实验性中风方法学以及对建议的中风干预措施的明显转化障碍也有重要影响。
