Estrogen therapy back in the lab
Richard White toiled in his laboratory at the Medical College of Georgia for eight years trying to understand how estrogen helped prevent heart attacks and stroke. His studies looked promising; estrogen seemed to prime the female cardiovascular system to prevent clotting and relax blood vessels.
So when the massive Women’s Health Initiative results were released three years ago -- finding that estrogen therapy in older postmenopausal women seemed to cause more heart attacks and strokes -- White was dumbfounded.
“It just didn’t make any sense,” says the pharmacologist. “But you can’t doubt it; the information was right there. So we started to try to figure out why this same hormone could produce two different effects.”
He went back to the drawing board, and so have a lot of other researchers.
A growing number of doctors are trying to reconcile the Women’s Health Initiative’s negative findings with other research suggesting estrogen therapy can’t be that bad.
These doctors say hormone replacement therapy may still be a valuable option for some younger women. They also say the recommendations emerging from the Women’s Health Initiative -- that hormone therapy should only be used in a low dose for the shortest time possible by women who need it the most -- may be needlessly restrictive.
“We used to think hormone replacement therapy should be taken by everyone,” says Dr. Hugh S. Taylor, an associate professor of obstetrics and gynecology at Yale University School of Medicine. “Now the pendulum has swung too far the other way.”
The Women’s Health Initiative was a randomized, controlled trial of 161,000 women designed in part to assess the effect of hormones on health. Before the study, doctors believed that estrogen protected women from bone fractures, heart attacks, stroke and dementia, improved skin tone and soothed the sometimes harsh symptoms of menopause.
The results, however, showed that study participants taking hormones had a slightly higher risk of heart attack and stroke as well as breast cancer. Hormone therapy did not appear to stave off dementia or even affect a woman’s quality of life, such as improving sleep or sexual satisfaction.
The age factor
But a growing number of doctors now say the study provides an incomplete picture because the average age of the participants was 63. If hormones are taken around the time of menopause -- age 51 on average -- they might protect women from heart attacks, stroke, an enlarged heart condition called cardiac hypertrophy and possibly even dementia, these experts say.
Two new studies have been launched to address that hypothesis.
“The WHI showed that if women have heart disease, by all means don’t give them estrogen. It will make things worse,” says Dr. S. Mitchell Harmon, director of the Kronos Longevity Research Institute in Phoenix. “But we still don’t know if estrogen is protective of a younger population group.”
Harmon is directing one of the new studies, called Kronos Early Estrogen Prevention Study, or KEEPS, that has begun recruiting newly menopausal women at eight U.S. medical centers. The privately funded study will place 720 women on one of three treatment regimens: oral estrogen, estrogen via a skin patch or a placebo.
All of the women taking estrogen will receive progesterone, which is given in combination with estrogen to prevent overgrowth of the uterine lining and possible uterine cancer.
Investigators will take periodic scans of the carotid and coronary arteries to measure the effects of hormone therapy on the development and progression of heart disease.
Another study is funded by the federal government to evaluate whether the effects of estrogen depend on when a woman starts estrogen therapy and whether a more natural form of estrogen, called estradiol, is safer.
The Early Versus Late Intervention Trial With Estradiol, or ELITE, study will recruit 504 Southern California women representing two groups: those within six years of menopause and those who are 10 or more years beyond menopause.
The women in the study will be followed to assess their cardiovascular health as well as any cognitive changes related to the development of dementia.
“I firmly believe the Women’s Health Initiative is not the final answer,” says Dr. Howard Hodis, principal investigator of the ELITE study and professor of medicine and preventive medicine at Keck School of Medicine, University of Southern California. “WHI has taken us to the next step. It has given us more questions we need to answer.”
Recent laboratory research bolsters evidence that estrogen acts much differently depending on a woman’s age. White, of the Medical College of Georgia, has demonstrated that as women age, estrogen can go from making nitric oxide, which protects the heart, to making a substance called superoxide, which damages tissues.
Those findings, published this month in the American Journal of Physiology, suggest hormone therapy could be tweaked so that estrogen continues to help produce the beneficial nitric oxide.
Another study, by UC Irvine researcher Dr. Vincent Procaccio, found that estrogen in pre-menopausal women appears to inhibit free radicals in the cerebral blood vessels that protect women from stroke. The finding, published in August in the online version of Molecular Pharmacology, could explain why pre-menopausal women have a lower incidence of stroke than men of the same age.
And Dr. Ellis R. Levin, a professor and vice chairman of the department of medicine at UC Irvine, recently showed that estrogen can help prevent cardiac hypertrophy, an enlarged heart condition that sometimes occurs in women who have had heart attacks. Levin’s study was published in July in the Journal of Biological Chemistry.
“No one would expect estrogen to undo the [cardiovascular] damage that has been done. But it’s going to prevent it from happening in the first place,” Levin says. “I think that is what many of us in the field believe. But we need the KEEPS data and other data that will definitely show this to us.”
Finding more answers
If the studies show estrogen does appear to benefit younger menopausal women, more questions will follow, experts acknowledge, such as how long a woman should take hormones to protect herself from heart disease or dementia.
Ongoing research on estrogen is important not just for possible prevention of heart disease, which is the leading cause of death in women, but because women and their doctors have been frustrated by the lack of alternatives to treat menopausal symptoms, says Taylor, who is an investigator in the KEEPS trial.
“There is nothing else that comes anywhere close to estrogen for treating hot flushes,” he says. “We trivialize these quality of life issues.”
But science may not be the only factor driving the increasingly drawn-out debate over the value of hormone therapy, suggests Michelle Naughton, an associate professor of public health sciences at Wake Forest University, who worked on the Women’s Health Initiative.
Earlier this year, Naughton coauthored a paper in the Journal of Social Issues exploring why hormone therapy continues to evoke controversy.
She argues that many “stakeholders” are having trouble accepting the lost promise of hormone therapy.
For example, the pharmaceutical companies have a financial stake in hormone products while doctors have a stake in meeting the needs of their patients. Women, who can expect to live a third or more of their lives after menopause, desire a high quality of life in their later years.
“I do think this debate is going to go on for quite some time because [the value of hormone therapy] is something that was so widely believed for many years,” she says.
