"It was right to close the Women's Health Initiative trial," said Judith L. Turgeon, professor of internal medicine at UC Davis School of Medicine and senior author of the Science article. "But we should not generalize the results of this trial and overlook the real potential that other forms of hormone therapy may offer to postmenopausal women."
The Women's Health Initiative trials used the steroid formulation most frequently prescribed in the United States at the time, given to women in pill form on a daily basis. New information gleaned from basic research in the biology of ovarian hormones, however, indicates that not all estrogens and progestins are alike, nor do they behave identically in different tissues in the body.
"As our understanding of the biology of these hormones grows, the more we realize how important certain factors are -- such as formulation, dosage, whether they're given by a pill or a patch, and characteristics of women being treated," said co-author Phyllis M. Wise, dean of the division of biological sciences and distinguished professor of neurobiology, physiology and behavior at UC Davis. "More targeted therapies may yield important health benefits."
Estrogens affect many tissues in the body. During natural menopause, which occurs in women at an average age of 51 years, estrogen and progesterone secretion from the ovaries diminish. Afterwards, the risk of coronary heart disease and osteoporosis increases. Stroke and dementia are also associated with aging.
"Estrogens and progestins provide women with important health advantages before menopause," said Turgeon. "We need to remain open to the possibility that these same ovarian hormones can help women stay healthier after menopause as well."
Hormone therapy was once thought to help postmenopausal women keep their health risks closer to levels seen in younger women. But prescribing such therapy has largely been abandoned by physicians after the Women's Health Initiative clinical trials found in 2002 that women on combination estrogen and progestin therapy had a slightly higher risk of heart attacks, strokes and blood clots than women taking a placebo. However, the study also found that the hormone therapy offered some protection against fractures and colon cancer. "Estrogens are important to maintain normal brain function and may protect against neurodegeneration," said Wise, who has conducted numerous laboratory studies on the protective effect of estrogens on the brain during aging and after injury. "There are so many potential benefits of estrogens and progestins after menopause that therapy with these hormones should not be disregarded based on a single study. Our goal is to find the right formulation and circumstances that will enable us to retain health benefits, while eliminating the risks."
There are many different estrogens and progestins, and each may have different effects. For example, the human ovary produces several types of estrogen, including estrone and estradiol. The estrogen preparation used most commonly for hormone therapy comes from horses and contains these as well as several other forms not secreted by human ovaries.
To add to the complexity, tissues throughout the body respond differently to the exact same estrogen or progestin. For example, tamoxifen, an estrogen-like drug used to treat breast cancer, blocks the effects of estrogen in the breast. However, it has the opposite effect in bones and the uterus, where it actually mimics estrogens.
"Subtle differences in hormone structure and subtle differences in cells can make a tremendous difference in outcome. This is why the effects of the specific estrogens and progestin used in the Women's Health Initiative may not apply to all estrogens and progestins," said Turgeon, who has done extensive research on steroid hormone action. "If we base all our conclusions on a single formulation, we are missing health benefits that may be conferred by different formulations and treatment regimens."
The researchers point out that how a drug is administered - by pill or patch, for example -- can also be critical to how it affects the body. For example, when estrogen is taken as a pill, as in the Women's Health Initiative study, it must first be processed through the liver, which responds by producing several proteins, some of which are associated with a higher risk of heart disease. However, when estradiol is administered through the skin with a transdermal patch, these proteins are not affected.
"More fundamental research of the roles of hormones in specific tissues are needed, and more clinical studies of different formulations and ways of administering the drugs are essential," said Turgeon. "A current thrust of pharmaceutical research is to create slightly different estrogen or progestin molecules to select for the biological effects we want to enhance." The other authors of the Science article are Donald P. McDonnell of Duke University Medical Center and Kathryn A. Martin of Harvard Medical School.
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