Reply to “Letter to the Editor: ‘Understanding the WHI gap’

Abstract

This is a reply in response to Drs. Kerber's and Turner's commentary about our article (10) in Physiological Genomics. We thank Kerber and Turner for their enthusiastic response to our article and are pleased that they found it useful in their practice (10). However, we would like to point out that the link between estrogen therapy postmenopause and a decrease in dementia in older women is tenuous at best. Few studies indicate definitively that hormone replacement therapy (HRT) results in a decrease in dementia, and most only point toward a possibility that has yet to be realized (5). Basic studies in rodent models suggest that estrogen replacement can reduce brain injury in models of stroke, but more work is needed before taking these findings to the clinical setting (1). Additionally, the Women's Health Initiative (WHI) and the Million Woman Study indicate that breast cancer risk increases significantly when women are put on HRT, specifically with estrogen and progesterone taken in combination, a finding that should limit the use of HRT to those women who do not already manifest a high risk for breast cancer (2, 9).

In contrast to chronic estrogen replacement, there is a small, but growing, literature supporting a role for a protective role of estrogen in acute injury (11–13). We and others have found that treatment with a high concentration of 17β-estradiol at the time of injury can greatly reduce inflammation and apoptosis (3, 4, 6, 14). Such limited use of E2 will not increase the risk of cancer but does have the possibility of greatly reducing tissue injury.

We feel that a more promising area for the treatment of postmenopausal symptoms comes from the selective estrogen receptor modulators (SERMs). For example, raloxifene improved verbal memory in postmenopausal women when given over a period of 5 yr.(7) In contrast tamoxifen, a SERM that is primarily an estrogen antagonist, was associated with poorer performance on letter fluency and manual dexterity in women with breast cancer compared with untreated controls (8). Many SERMs have been synthesized, and some may have the positive, protective effects of estrogen without promoting cell proliferation and cancer. More work will be needed identifying the specific effects of these compounds before this type of treatment can be applied in the clinic to ameliorate aging-associated changes such as cardiovascular disease and dementia