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Department of Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Dr. Gloria Hoffman, Department of Anatomy and Neurobiology, University of Maryland, 685 West Baltimore Street, Baltimore, Maryland 21021. E-mail: gehoffman{at}umaryland.edu.
We are led to believe that, for women during menopause, there are no good choices. The failure of the ovaries to produce estrogens results in hot flushes and/or sleep disturbances in many women, as well as accelerated bone loss, increased risk of colon cancer, and weight gain accompanied by shifts in plasma lipoprotein cholesterol profiles associated with a higher incidence of cardiovascular disease. However, replacing estrogens is associated with increased risks of uterine and breast cancer (perhaps ovarian cancer as well) and clotting disorders. Meanwhile, longstanding data make clear that there are benefits that estrogens can have on bone density and plasma lipid profiles after menopause, and converging evidence shows widespread benefit of estrogens in the central nervous system in not only eliminating the hot flushes and sleep disturbances that can accompany menopause but also in improving memory (1) and protecting neurons from cell death (Refs. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and Hoffman, G. E., W. W. Le, A. Z. Murphy, and C. L. Koski, submitted manuscript).
Conventional hormone replacement therapies come in a number of forms. The most widespread in the United States has been a combined preparation of equine-conjugated estrogens along with a synthetic progestin (medroxyprogesterone acetate, MPA), a single pill preparation ideal for patient compliance. However, the National Institutes of Health, in a large multicenter trial (the Women’s Health Initiative), evaluated the combined preparation of conjugated estrogens and MPA and found that it did not improve risk for stroke and increased slightly the risk for breast cancer (17, 18), leading to the recommendation within the medical community that hormone replacement therapy be avoided altogether or be used only for a limited period of time. This recommendation may be inappropriate when applied to hormone replacement that employs other hormone regimens because conjugated estrogens are not the same as 17ß-estradiol (the major natural estrogen the young ovary synthesizes); medroxyprogesterone acetate has not only progestin-like activity but can function as an androgen as well (19, 20); and constant exposure to estrogens and progestins does not mimic the cyclic secretion of hormones. Next, many women have used either oral-conjugated estrogens or transdermal 17ß-estradiol along with intermittent oral progestins (comprised of either oral MPA or transdermal micronized progesterone), a better model for cyclic hormone patterns, but large trials comparing this approach to the one used in the Women’s Health Initiative have not been conducted. There are alternative plans less widely used in our country. One is transdermal 17ß-estradiol and intrauterine progestins, a plan that has been widely prescribed in Scandanavian and other countries, and this approach may circumvent some of the problems encountered with the combined oral delivery of the conjugated estrogens and MPA (21). In addition, a growing number of women have turned to use of plant estrogens, but that regimen is difficult to assess. An obvious problem in evaluating plant preparations is the variability of active drug in either soy products or the over-the-counter preparations, making controlled evaluation difficult and efficacy questionable. Although there are multiple reasons to favor one preparation over another in considering hormone replacement therapy, given the known impact of estrogens on proliferative tissues, it is unlikely that any long-term estrogen therapy would avoid completely the risk of carcinogenesis in the uterus or breast. On the other hand, it is equally unlikely that any single drug could easily replace estrogen’s beneficial effects on bone, lipid metabolism, and the central nervous system (CNS). Is there no hope?
The study by Labrie et al. (22) offers compelling evidence that use of a selective estrogen receptor antagonist (EM-652) in combination with 17ß-estradiol enables beneficial effects of estrogens on the bone and plasma lipid profiles while at the same time blocking proliferative effects in the mammary glands and uterus. Although the authors argue that the antagonist poorly enters the CNS, a recent study (23) indicated that EM-652 did affect certain estrogen actions on gene expression in the hippocampus and hypothalamus. Because that study did not evaluate any of the neuroprotective effects of estrogen in the CNS, it is difficult to predict whether the observed effects have direct relevance to the issues of menopause and the brain. Obviously, if the regimen proposed by Labrie et al. (22) is to be useful in post menopausal women, more work is required to ensure that the CNS effects of estrogen are maintained in the presence of the inhibitor and that the combination of estrogen and EM-652 is still effective after very long-term use. Nonetheless, the study provides an exciting avenue worth pursuing in this important arena.
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Received August 5, 2003.
Accepted for publication August 20, 2003.
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