Estrogen: a neuroprotective or proinflammatory hormone? Emerging evidence from reproductive aging models

Estrogen or hormone (estrogen + progestin) replacement is typically prescribed to women for relief from vasomotor symptoms at menopause. Observational studies have shown that such replacement also decreases the risk for Alzheimer's disease. Experimental data from a variety of animal models also suggest that estrogen replacement given to ovariectomized animals is largely neuroprotective. However, the recent intervention trial (Women's Health Initiative Memory Study; WHIMS) concluded that estrogen replacement and hormone replacement prescribed to postmenopausal women increased the risk for global cognitive impairment and dementia, respectively. This paper will examine evidence that the disparity in the human and animal data can be reconciled by consideration of the "reproductive" age of the individual receiving estrogen or hormone replacement. Our recent studies comparing the effects of estrogen replacement on young adult animals with those of estrogen replacement to reproductive senescent animals suggest that the estrogen replacement is beneficial when given to "surgically menopausal" (ovariectomized) animals. However, estrogen replacement appears to be deleterious to acyclic reproductive senescent animals, where target organs such as the brain have been in a prolonged estrogen-deficient state. The paper will also review aging and reproductive age-related changes in the estrogen receptor (ER) systems, specifically ER-alpha, as a potential mechanism for estrogen's deleterious effects in the reproductive senescent animal.