Hormone replacement therapy has attracted a lot of attention over the past few years. A combination of progestin and estrogen therapy was believed to reduce dementia and stroke, and other risks associated with aging such as heart attacks. A 2002 report on preliminary outcomes from the Women’s Health Initiative changed this belief (Fletcher and Colditz). This report included data from 16,000 post-menopausal women collected at various sites throughout the US. The authors concluded that hormone combination therapy increased the risk of heart attack, stroke, cancer, and blood clots and had numerous ramifications in the medical community. Estrogen therapy alone continued to be studied, but was also found to carry significant risks to health including increased risk of dementia and stroke (Anderson et al.). The biological mechanisms behind these finding are still unclear, however there is some evidence that estrogen has varying effects across the lifespan in females.
Estrogen can be neuroprotective in the brain by reducing the size of infarct and neuronal death after stroke in animal models (Jover et al.; Rau et al.). This is generally studied in healthy, young animals and not aged animals; which may partially account for the discrepancies between findings in animals and humans. It is unknown if the neuroprotective effects of estrogen are mediated through cells in the brain, such as microglia, or immune cells in the periphery, such as leukocytes.
A recent report(Johnson and Sohrabji) sought to determine if estrogen dampens inflammation by reducing the immune response in peripheral immune cells and/or brain derived cells (microglia) from young and old female rats.
The authors used two groups of rats: young adult females (four months) and reproductively senescent females (13-16 months). Ovaries were removed and replaced with pellets secreting estradiol resulting in physiological levels of circulating estrogen. Microglia from the brain and blood cells were removed and cultured separately in the lab to asses the effects of immune stimulation in each cell population. Immune activation was induced through administration of Lipopolysaccharides (LPS) and the amounts of pro-inflammatory cytokines (immune signaling molecules) were measured.
Johnson & Sohrabji found that estrogen could not attenuate the immune response in microglia in either age group. However, estrogen could attenuate the peripheral immune response in young females, but increased cytokine production from peripheral immune cells in aged females. The authors also report that this effect is only found after chronic pretreatment, and mention unpublished results suggesting that acute estrogen treatment after inflammation has no effect.
What does this mean in terms of hormone replacement therapy? These findings suggest that estrogen is neuroprotective in young females, and that estrogen restrains neural inflammation through suppression of circulating immune cells in the periphery. In humans, immune cells from post-menopausal women secrete higher levels of pro-inflammatory cytokines than pre-menopausal women (Schurman et al.). These results suggest that when estrogens are given to older women, they are likely to increase pro-inflammatory cytokines, which could potentially increase neurodegenerative events in the brain. A separate report has shown that cognitive impairment in the elderly are associated with higher amounts of pro-inflammatory cytokines (Yaffe et al.). In summary, it is clear that estrogen replacement therapy has benefits in young females, but these same benefits may not occur in aged females.