Hormone Replacement Turmoil
For most women, the facts behind the furor over hormone replacement therapy leave plenty of questions still unanswered.
It has never been easy for women to make decisions about hormone replacement therapy—HRT—after menopause. That is hardly surprising, considering that calculating the risks and benefits of ingesting daily doses of estrogen and/or progestin has stymied even the most proficient of statisticians. And research scientists have been equally perplexed while trying to compare such medical apples as breast and endometrial cancer to research oranges like heart disease and stroke.
Then came the announcement in early July 2002 that the National Institutes of Health had halted a portion of an ongoing trial of the effects of hormone replacement therapy in postmenopausal women. Its researchers found a small—but, they said, significant—increase in the risks of breast cancer, heart attack, blood clots and strokes after five years among the combination HRT users as compared with non-users.
The announcement was met with a media frenzy, causing the 6 million postmenopausal women taking HRT in the United States—and millions of others worldwide—to rethink their carefully considered decisions. “I’ve been inundated with calls,” says Donna Shoupe, M.D., professor of obstetrics and gynecology at the
Keck School of Medicine of USC. “Hundreds upon hundreds of calls.”
The study that caused all this fuss was an arm of the large-scale, long-term Women’s Health Initiative that was following 16,608 postmenopausal women, ages 50 to 69.
The women were supposed to take either estrogen and progestin (in the form of the top-selling HRT preparation, a combination of the estrogen derived from pregnant mares’ urine along with synthetic progesterone) or a placebo. According to its authors, who published the results of the trial in the Journal of the American Medical Association (JAMA) on July 17, 2002, the women who took the combination hormone pill for five years had 26 percent more cases of breast cancer than those on placebo; in addition, they had twice the number of blood clots, 41 percent more strokes and a 29 percent higher incidence of heart disease.
There were some positive results: colorectal cancer rates in the HRT group and hip fractures as a result of osteoporosis were about a third less than in the placebo group. And there was no difference in cardiovascular or overall mortality between the groups. The researchers noted that those positives, however, did not balance out the negatives; they said they had no choice but to bring this portion of the study to a close, almost three years early.
The study shutdown may have sent shockwaves across the country, but to many of the researchers at the Keck School of Medicine, the news came as no great surprise—and was roundly seen as having been overplayed and overhyped.
Breast cancer rise
“The Women’s Health Initiative study really just confirmed what we at USC had shown definitively in 2000, at least in terms of breast cancer,” says Ronald K. Ross, M.D., professor of preventive medicine and the Flora L. Thornton Chair in Preventive Medicine. “Our group here showed that the risk of breast cancer in women taking combination therapy was four times that of women taking estrogen-only hormone replacement therapies.”
That study, published in the February 16, 2000, issue of the Journal of the National Cancer Institute, looked at 1,897 postmenopausal women from Los Angeles County who were diagnosed with breast cancer in the late 1980s to mid-1990s, and compared them to 1,637 similar women without breast cancer. Among the things the women were asked about was their use of hormone replacement therapies.
What the Keck School research group—which included Ross, Annlia Paganini Hill, Ph.D., professor of preventive medicine, and Malcolm Pike, Ph.D., professor of preventive medicine—found was that for every five years women use estrogen replacement therapy, their risk of breast cancer increases six percent, a statistically insignificant increase. But what was striking was that for women using both estrogen and progestin, the risk of breast cancer rose 24 percent after five years, an increase that was statistically significant.
“Our epidemiological studies anticipated the results observed in the WHI,” Ross says. “We began to argue in the 1980s for the development of a strategy to deliver progestins so as to maximize exposure of the endometrium and minimize, or eliminate, exposure to other organs.” The Women’s Health Initiative is still studying the question of increased risk for women taking only estrogen—information that could be critical in reassessing the use of hormones after menopause. “Everything we’ve looked at so far indicates that those data are going to be much more favorable.” Ross says.
Similarly, the JAMA paper notes that the arm of the study looking at women taking only estrogen showed no significant cancer or cardiovascular risks to date, and so will continue until March 2005.
Helping hearts
Howard N. Hodis, M.D., professor of medicine and preventive medicine, has seen first-hand the protective effects of replacing estrogen with bio-identical 17beta-estradiol. In his area of interest—the heart—Hodis and his team at the USC Atherosclerosis Research Unit found that unopposed 17beta-estradiol therapy appears to reduce atherosclerosis progression in healthy, postmenopausal women.
Before menopause, estrogen seems to protect women from most of the risk of heart attack and stroke that hangs over the heads of men. “In premenopause, there is little clinical manifestation of atherosclerosis in women,” says Hodis. “But when a woman hits menopause, her risk in a short period of time becomes equal to that of men.”
Cardiovascular disease is the number one killer of women, striking down more women than cancer and all other causes combined.
The USC study, called the Estrogen in the Prevention of Atherosclerosis Trial, or EPAT, looked at the progression of atherosclerosis over two years in 222 healthy women who took unopposed 17beta-estradiol, a form of estrogen identical to that made by human beings, or placebo early in menopause. What they found, says Hodis, is that “these women had a significant reduction in the progression of atherosclerosis, a change that translates into a reduced risk for future cardiovascular events such as heart attacks and strokes.”
No fear
So, what is a woman to do? “Don’t panic,” says Dan Mishell Jr., M.D., the Lyle G. McNeile Professor of Obstetrics and Gynecology and chair of the Department of Obstetrics and Gynecology at the Keck School of Medicine. “I don’t think we should throw out the baby with the bath water just because of this one study,” he told the New York Times after the study stoppage was announced.
As Mishell points out, the Women’s Health Initiative study is simply another factor to use in making an already-complicated decision. If you are already on HRT and you are worried, you should talk to your physician about whether it is in your best interest to continue the therapy. On the other hand, if you are not taking HRT, but are suffering with some of menopause’s more burdensome effects—hot flashes, decreases in libido, an increasing risk of bone fracture—you might want to talk to your physician about whether there is a form or dose of HRT that might be right for you.
After all, there are a variety of hormone preparations aside from those tested in the Women’s Health Initiative, and there are different routes by which they can be delivered.
“I think the Women’s Health Initiative study was designed to answer some very important questions,” Shoupe says. “But it was limited to one form of medication that was given to older patients. In the end, it was a limited study in terms of the information we can really derive from it.”
There are, of course, cases in which women should definitively not take HRT;
if a woman has a history of breast cancer, uterine cancer, blood clots or stroke, this is not the therapy for her, Mishell says.
On the other hand, fears of increased cancer and other health risks do not have to mean that a woman cannot use HRT at all. Shorter-term therapy may be appropriate for women in whom menopausal symptoms are harming quality of life, he says.
One fact most researchers are beginning to agree upon is that HRT probably gives the greatest benefit in the time just after the onset of menopause, when hormone levels drop and symptoms such as hot flashes appear. “The problem with starting estrogens later is that bone loss occurs at a much higher rate right after menopause,” Ross says. “So any bone loss from those years cannot be recovered by starting estrogen therapy later.”
The same may be true of cardiovascular disease prevention for women, Hodis adds. Looking at the findings on bone loss, he says, leads him to believe that “the best time to prevent atherosclerosis is likely to be right at the beginning of menopause.” And the best way to go about that prevention, he adds, may be to give the women unopposed estrogen in low doses or transdermally— as opposed to estrogen-progestin combination pills.
“It is important to understand that the halted trial only studied one form of HRT, one preparation,” says Hodis. “It did not address low-dose therapy, bio-identical therapies, or other hormone types, regimens or delivery routes, such as transdermal delivery. It only studied hormone types not found in humans, and it studied only one regimen, where estrogen and progestin are given together every day. Further, women in the Women’s Health Initiative were started on HRT at an average age of 63, more than 10 years after menopause. Not only is this rarely done in clinical practice, but under these circumstances the study became one of treatment for atherosclerosis—which the statin drugs already do well—rather than prevention.”
If a woman does opt for HRT, how long should she stay on it? “All of the chronic effects we’re talking about—cancer risk, prevention of bone loss, prevention of cardiovascular disease—are duration-related,” says Ross. “We don’t know enough yet to say exactly where it balances out for each individual patient.”
Shoupe prefers to start patients with the lowest possible doses of the hormones and keep them on the therapy indefinitely. “If you over-interpret this study, if you just say ‘estrogen is bad,’ then you’re going to lose some of the big advantages of estrogen therapy,” says Shoupe. “I have these wonderful, healthy patients in their 70s, and they simply don’t get the estrogen-deficiency diseases. Estrogen in low doses is great at preventing things like bone loss, skin changes, urogenital atrophy, accelerated atherosclerosis and even dementia.”
Of course, Shoupe notes, that does not mean that she is unconcerned about the potential effects of HRT: She says she regularly monitors her patients, keeping an eye on their health via mammograms, bone scans and pelvic ultrasounds.
“I’m letting my patients make their decision on their own,” Shoupe says, “but I am trying to give them my take on the study, to give them an overview of what’s going on. I just really believe that low-dose estrogen is a very valuable tool for many menopausal and postmenopausal women. If the Women’s Health Initiative study has convinced me of anything, it convinced me to try using even lower doses of estrogen, to balance the effects of the hormones.”
Subir Roy, M.D., professor of obstetrics and gynecology at the Keck School, agrees that the NIH study really needs to be taken with a grain of salt. “The study had a rather arbitrary design,” he says. “For one thing, they used a single dose of HRT for all the women. Ob/GYNS don’t just give all women a standard dose of hormones—we treat the individual. In addition, the study was composed of women who are significantly older, rather than in recently menopausal women.”
What is important to remember, Roy continues, is that HRT has a number of significant benefits—from protection against osteoporosis and dementia to a reduction in tooth loss, colon cancer and genitourinary complaints. In addition, he notes, HRT seems to increase a woman’s overall sense of well-being, and can—when taken via a skin patch—actually increase sex drive in some women. [See Benchmarks, page 32.]
“All these data really tell us is not to use a single, high dose of HRT blindly in older individuals,” Roy says. “And we already knew that.”
Still, notes Ross, the Women’s Health Initiative study—for all its limitations—focused attention on a number of important questions and raised issues about the safety and efficacy of various forms and preparations of hormone replacement therapy that will now be looked at carefully.
“For those of us who have spent a good part of our lives working on these issues,” Ross says, “we tend to think we know a lot about the risks of hormone replacement therapy, especially with regards to breast cancer. And we do know a lot. But the reality is, we’ll likely learn a whole lot more during the next decade or so. There’s always more to learn.”
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