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Abstract & Commentary
Synopsis: Using a mouse model of ischemic stroke, the researchers demonstrate that ERa, but not ERb, mediates the neuroprotective effects of estradiol exposure.
Source: Dubal D, et al. Proc Natl Acad Sci Am. 2001;
Dubal and associates have been exploring the mechanisms by which estrogen confers neuroprotection. They previously demonstrated that the neuroprotective effects of 17b-estradiol are not rapid and require a period of pretreatment, suggesting that ER-mediated alteration of gene expression is required to afford neuroprotection. Furthermore, in response to ischemic injury, ERa mRNA is up-regulated in the brain in the presence and the absence of estradiol. In contrast, injury down-regulates ERb mRNA, and this down-regulation is prevented by advance estradiol exposure. Finally, this investigative team has shown that the estrogen isomer 17a-estradiol, which has 100-fold less affinity for ERs, fails to protect against brain injury and that the protective effects of 17b-estradiol are prevented by ICI 182,780, an ER antagonist. To further define the role of ERa and ERb in mediating the neuroprotection effects of 17b-estradiol, they examined the effects of estradiol in genetically modified mice lacking either ERa or ERb. Knock-out (KO) mice were compared to their respective wild-type strains. Ovariectomy was followed by estradiol replacement to a standard physiological level or placebo. One week later, ischemia was produced and then the mice brains were examined histologically after 24 h. During the ischemia, doppler monitored cerebral blood flow. In both wild-type strains, estradiol decreased total ischemic injury by more than 50% compared with oil-treated controls. In ERaKO mice, estradiol failed to exert any protection against infarct. In marked contrast, in ERbKO mice, estradiol exerted profound protective effects against brain injury. The results were not explained by differences in cerebral blood flow during or after the ischemia.
COMMENT by Sarah L. Berga, MD
This study bears directly on the decision as to which estrogen is best for long-term use by postmenopausal women. If the results of this study hold for humans, then what is needed is an agent that acts via ERa. One such agent is 17b-estradiol. Compounds that are antagonists for ERa are unlikely to protect against ischemic CNS injury. One such agent is raloxifene. Phytoestrogens bind predominantly to ERb. Thus, while it might be advantageous to incorporate them into one’s diet (see Clarkson study reviewed in the April 2001 issue of OB/GYN Clinical Alert), but they are unlikely to be a worthy replacement for estradiol. A prime benefit of agents that are ERa antagonists is that they don’t stimulate endometrial growth. As reviewed earlier this year, however, the vaginal tissues, including the smooth muscle cells, predominantly express ERa.1 Thus, while it is nice to think we might find an agent that doesn’t stimulate endometrium, it seems unlikely that any such agent will confer full neuroprotection or even ameliorate genitourinary atrophy. At the risk of sounding brazen, I would like to suggest that it is easier to do a hysterectomy for endometrial hyperplasia or persistent breakthrough bleeding than it is to restore an infarcted brain. Perhaps we will never find the perfect agent. In the meantime, it seems prudent to recommend the estrogen that mother nature designed for women, namely, 17b-estradiol, given in physiological doses.
1. Pelletier G, El-Alfy M. J Clin Endocrinol Metab. 2000; 85:4835-4840.