Since Ed Hall and colleagues first discovered that female gerbils were relatively protected from global cerebral ischemia, compared with their male counterparts, in the early 1990s (Hall et al., 1991), gender differences have been a major focus of neurological research. Intriguingly, according to Scott et al. (2012), “gender differences exist in most disorders affecting the central nervous system (CNS), particularly the neurodegenerative conditions, with women typically having a later onset and greater severity of disease (Tang et al., 1996, Brann et al., 2007). Women’s relative protection, later onset, and greater severity of neurodegenerative disorders can be explained, in part, by serum levels of the neuroprotective ovarian hormone, 17p~estradiol (estradiol or E2). From birth to menopause, women’s ovaries produce high circulating levels o f estradiol, which correlates with a low incidence o f neurodegenerative disease. However, once the menopausal transition occurs, the ovaries cease to [produce] E2, and women’s risk for neurodegenerative diseases, including ischemic stroke and Alzheimer’s disease, increases (Brann et al., 2007). One could dismissively attribute this correlation to senescence. However, women who enter menopause prematurely via bilateral oophorectomy (surgical removal of both ovaries) have a doubled lifetime risk for developing dementia, as well as a significantly increased risk of cognitive decline, Parkinson’s disease, and mortality from neurological disorders (Rocca et al., 2007, Shuster et al., 2010, Rocca et al., 2011). Furthermore, meta-analyses of observational studies demonstrated that postmenopausal women who used oral estrogens had a 29-44% reduced risk o f Alzheimer’s disease (Yaffe et al., 1998, Hogervorst et al., 2000, Brann et al., 2007).
In further support of the correlation between high serum levels of estradiol and women’s relatively low risk of neurodegenerative disease, studies in rodents have overwhelmingly demonstrated that E2 is a neuroprotective agent. Female rodents were less susceptible to ischemic stress via experimental stroke procedures, such as middle cerebral artery occlusion (MCAO) and global cerebral ischemia (GCI), than their male counterparts, and ovariectomy prior to stroke induction abolished this gender difference (Brann et al., 2007). Serum E2 levels in intact rodents were also found to be inversely correlated with stroke infarct size (Liao et al., 2001), and pre-treatment with ICI 182,780, a competitive antagonist of both estrogen receptor isoforms alpha (ERa) and beta (ER(3), prior to stroke induction actually enhanced the size of the infarct (Sawada et al., 2000). Additionally, pre-treatment with aromatase inhibitors, which prevent the conversion of androgens to estrogens, exacerbated ischemic injury in rodent brains, and aromatase knockout (KO) mice, which are physically unable to convert testosterone into estradiol, also had larger infarct volumes after MCAO (McCullough et al., 2003). Conversely, pretreatment with exogenous E2 decreased mortality and infarct size following MCAO and GCI in rodents (Simpkins et al., 1997, Dubai et al., 1998, Shi et al., 1998, Zhang et al., 1998, Rusa et al., 1999, Jover et al., 2002, Shughrue and Merchenthaler, 2003, McCullough et al., 2005, Brann et al., 2007, Zhang et al., 2008, Lebesgue et al., 2009, Zhang et al., 2009a, Yang et al., 2010, Zhang et al., 2011). A systematic review o f 161 publications on estradiol and stroke performed by Gibson et al. further confirmed a dosedependent reduction of stroke lesion volume by E2 in models of transient and permanent cerebral ischemia (Gibson et al., 2006).
Aside from preventing neuronal death, exogenous E2 replacement prior to stroke was shown to attenuate behavioral deficits in ovariectomized female rats subjected to GCI (Plamondon et al., 2006, Brann et al., 2007, Lebesgue et al., 2009). Furthermore, exogenous E2 was shown to facilitate post-stroke recovery in mice by enhancing neurogenesis in the dentate gyrus and subventricular zone after stroke, an effect that was attenuated in estrogen receptor (ER) knockout (KO) mice and aromatase KO mice (Li et al., 201 lb). As reviewed previously by our group and others, E2 has also been demonstrated to afford protection in animal models of Parkinson’s disease and
Alzheimer’s disease (AD) (McCullough et al., 2003, Brann et al., 2007, Bourque et al., 2009, Pike et al., 2009). Finally, it should be mentioned that there are dissenting studies in the literature, which found that E2 increased ischemic stroke damage in animal models (Harukuni et al., 2001, Carswell et al., 2004a, Bingham et al., 2005, Gordon et al., 2005, Theodorsson and Theodorsson, 2005, Yong et al., 2005). It is not completely clear as to why these studies yielded a different result than the majority of studies in the literature, but a recent review suggested that the difference could be due to use of E2 slow-release pellets that yielded unexpectedly high circulating E2 levels (Strom et al., 2009). Nevertheless, as a whole, research using animal models provides strong evidence for endogenous and exogenous E2 as a neuroprotective agent,” (pp. 85-86) (Scott et al., 2012).
Reference: Erin LeeAnn Scott. MOLECULAR MECHANISMS UNDERLYING ENHANCED RISK OF NEUROLOGICAL DISEASE FOLLOWING PREMATURE MENOPAUSE