Does Short-Term Estrogen Therapy Produce Lasting Benefits in Brain?

The question of whether estrogen therapy should be used in postmenopausal women is a topic filled with controversy and debate. In vitro and animal studies clearly show that estrogens (most often 17 -estradiol) are neuroprotective (1), can enhance hippocampal and cortical function (2), improve cognitive performance (3), and prevent or reduce age-related cognitive decline (4, 5). Estrogen therapy, however, is not without risks. These include increased production of liver proteins such as sex hormone-binding globulin and C-reactive protein as well as increased risk of thromboembolism and stroke and breast and uterine cancers (6–9). Although positive effects on cognitive performance have been observed (10), negative results also have been reported. For example, the recent Women’s Health Initiative Memory Study showed an increased ( 2-fold) risk of dementia among women receiving the combination of oral conjugated equine estrogens and medroxyprogesterone acetate (11) and a trend toward increased risk of dementia among women receiving conjugated equine estrogens alone (12). This was a very large study of over 7000 women with a mean age of 69 yr. Another recent study likewise showed increased risk of cognitive decline among long-term users of estrogen therapy, particularly among women who initiated therapy at older ages (13). These findings have raised serious concerns about the long-term use of estrogen therapy in older postmenopausal women. As a result, women who are prescribed therapy for the treatment of menopausal symptoms are encouraged to limit therapy to the lowest possible dose and duration. But might short-term therapy initiated around the time of menopause confer some lasting benefit to the brain? Quite possibly so, according to a recent report by Rodgers et al. (14). The authors tested whether treating rats with estradiol for 40 d after being ovariectomized at middle age would have lasting benefits on working memory performance months after discontinuing the hormone treatment. Results show that 40 d treatment initiated at the time of ovariectomy was as effective as sustained treatment at enhancing working memory performance when rats were tested 1, 3, 5, and 7 months after discontinuing hormone. This finding demonstrates that, in rats, a relatively brief course of hormone therapy initiated in middle age can have long-lasting benefits on cognitive performance. The implications of this observation are profound. Estrogen therapy is proven to be very effective at mitigating perimenopausal symptoms that, for many women, result in significant improvements in quality of life during the perimenopausal transition (7, 15). Some of the risks of estrogen therapy can be mitigated by using transdermal as opposed to oral therapy (16). Adding a progestin will mitigate the increased risk of uterine cancers but may increase the risk of breast cancer (17). Given the concerns, women and physicians are faced with the difficult task of assessing on an individual basis not only the immediate benefits of hormone therapy but also the risks and benefits of an extended course of treatment. Rodgers’ findings, if true in humans, would provide another important benefit of short-term estrogen therapy during the perimenopause, namely a lasting benefit on cognitive performance. What is the likelihood that a lasting benefit of estrogen therapy on brain function occurs in humans? Several observational studies have reported that past postmenopausal use of estrogen therapy is associated with significant reductions in the risk of developing Alzheimer’s disease (AD) among older postmenopausal women (18). One study evaluated 1866 women living in Cache County, Utah, with a mean age of approximately 74.4 yr (19).