Revisiting the timing hypothesis: Biomarkers that define the therapeutic window of estrogen for stroke

Abstract

Significantly extended life expectancy coupled with contemporary sedentary lifestyles and poor nutrition have created a global epidemic of cardiovascular disease and stroke. For women, this issue is complicated by the discrepant outcomes of hormone therapy (HT) for stroke incidence and severity as well as the therapeutic complications for stroke associated with advancing age. Here we propose that the impact of estrogen therapy cannot be considered in isolation, but should include age-related changes in endocrine, immune, and nucleic acid mediators that collaborate with estrogen to produce neuroprotective effects commonly seen in younger, healthier demographics. Due to their role as modulators of ischemic cell death, the post-stroke inflammatory response, and neuronal survival and regeneration, this review proposes that Insulin-like Growth Factor (IGF)-1, Vitamin D, and discrete members of the family of non-coding RNA peptides called microRNAs (miRNAs) may be crucial biochemical markers that help determine the neuroprotective “window” of HT. Specifically, IGF-1 confers neuroprotection in concert with, and independently of, estrogen and failure of the insulin/IGF-1 axis is associated with metabolic disturbances that increase the risk for stroke. Vitamin D and miRNAs regulate and complement IGF-1 mediated function and neuroprotective efficacy via modulation of IGF-1 availability and neural stem cell and immune cell proliferation, differentiaton and secretions. Together, age-related decline of these factors differentially affects stroke risk, severity, and outcome, and may provide a novel therapeutic adjunct to traditional HT practices.

Sex differences in cognitive impairment and Alzheimer’s disease

“…This observation prompted the consideration of the timing of estrogen therapy relative to the onset of the menopause. In fact, a growing number of studies [280; 281; 282] support the existence of the “window of opportunity hypothesis”, which states that there is a limited period after the menopause during which ET or HT is effective. In view of these new studies and others, it would appear that ET may not have universal utility in treating/preventing dementia.…”

Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury

“…Whether the anti-inflammatory effects of 17βE2 persist following reproductive senescence (in rodents) or menopause (in humans) is under intense investigation. The majority of studies suggest that these effects do not persist in older female rodents (Leon et al, 2012; Sohrabji et al, 2013b; Strom et al, 2011). In addition to the loss of the anti-inflammatory properties of 17βE2 in young, Ovx mice, recent studies strongly suggest that the anti-inflammatory effects of 17βE2 are lost during a period of prolonged hypoestrogenicity in middle-aged (Suzuki et al, 2007a), or reproductively senescent (Selvamani and Sohrabji, 2010a; Sohrabji et al, 2013a), mice.…”

Window of opportunity: Estrogen as a treatment for ischemic stroke

“…Therefore, there might be additional factors that contribute to the discrepancy between the experimental studies and clinical trials. More recently, a biomarker window hypothesis was introduced as the loss of endocrine factors as Vitamin D and IGF-1 might alters the effects of hormone therapy with the postmenopausal demographic in the context of stroke (Selvamani and Sohrabji, 2010a; Selvamani and Sohrabji, 2010b; Selvamani et al, 2012; Sohrabji et al, 2012). In addition, the beneficial action of estrogen might be counter balanced by its action on coagulation and fibrinolysis, which might further affect the incidence of stroke and cardiovascular event and the progression of vascular dementia.…”