Effects of Sex Steroids on Stroke

Yang, Shaohua, Effects of Sex Steroids on Stroke. Doctor of Philosophy (Biomedical Science), February 2004, pp210, 5 tables, 27 illustrations, 64 titles. Estrogens and androgens are recognized as major sex steroids for females and males, respectively. However, it is clear that estrogens as well as androgens are more than gender hormones. Our data indicated that female steroids, such as 17β-estradiol (E2), exert neuroprotective effects on stroke, while male steroids, like testosterone, exert deleterious effects on stroke. The neuroprotective effects of estrogens have been very well demonstrated both in vitro as well as in vivo. Our studies indicated that neuroprotective effects of E2 are exerted both ischemic and hemorrhagic stroke. In our subarachnoid hemorrhage (SAH) model, E2 reduced secondary ischemic damage and mortality consequent to SAH. These effects were not associated with the change of the clot volume in SAH. The neuroprotective effects of estrogens were not only seen in the pre-treatment paradigms. E2 exerted neuroprotective effects even when administered after ischemia, with a therapeutic window of about 3 hours in a permanent focal cerebral ischemia model. This effect of estradiol was associated with no immediate change on blood flow, but with a delayed increasing in cerebral blood flow (CBF). Further our studies indicated that a non-estrogen receptor (ER)-binding analogue possessed both neuroprotective and vasoactive effects, which suggests that both the neuroprotective and vasoactive effects of estrogens are receptor-independent. This molecule also offers the possibility of clinical application for stroke without the side effects of estrogens. We used immunochemistry, immunoblot and mass spectrometry to demonstrate that ERβ is localized to mitochondria. Our data established this ERβ localization in a variety of cell types, suggesting that ERβ is not a nuclear receptor, which was thought to mediate the genomic function of estrogens. In contrast to estrogens, testosterone increased neuronal toxicity and exacerbated cerebral ischemia-reperfusion injury. These results suggest that sex differences in outcome after stroke may result from both the protective effects of estrogens and the damaging effects of testosterone. Further, our study indicated that stress induced testosterone reduction contributes to cerebral ischemia tolerance against ischemia reperfusion injury, providing the first in vivo evidences for a neuroendocrine mechanism for the cerebral preconditioning in males.