Estrogen on Trial

Susan Sullivan doesn’t know whether her health would be helped or harmed by hormone replacement therapy.

But the 55-year-old Topanga Canyon artist is counting on one thing: By the time her 20-year-old daughter reaches menopause, there will finally be some solid, trustworthy medical information about who should be on hormones and why.

Like most U.S. women over age 45, Sullivan has watched with apprehension as studies made public during the last few months have presented disturbing and contradictory findings, leaving many women confused about the risks and benefits of using hormones.

Sullivan is doing her small part to bring some clarity to the confusion. She visits UCLA Medical Center several times a year to participate in the largest study to date of the medical impact of hormone therapy in women.

“When I arrived at menopause, I found there wasn’t any good information out there,” Sullivan says. “But I have a daughter, and I thought her generation deserves better.”

Known as the Women’s Health Initiative, the federally funded study involves 161,000 women between the ages of 50 and 79, as well as researchers at more than 40 sites. The 15-year, $700-million study (which looks at other women’s health issues besides hormone therapy) is considered a crown jewel in current women’s health research.

“The Women’s Health Initiative is the only [scientifically rigorous] trial that actually looks at the effect of estrogen on bones, brain, heart and other issues, including types of cancers,” says Michele Blackwood, a breast surgeon in Stamford, Conn.

Other recent studies have greatly complicated the question of who should take hormones. Among the findings:

* Two epidemiological studies found that the risk of breast cancer increases the longer women take hormones.

* A small, short-term study of women with Alzheimer’s disease showed that, after 16 weeks, there was no apparent benefit from hormones in reducing symptoms of the disease. Earlier studies, however, have indicated that estrogen may be helpful for Alzheimer’s.

* A major, long-term study of post-menopausal women with heart disease, called the Estrogen Replacement and Atherosclerosis (ERA) study, showed that hormone use did not slow the course of the disease.

If those results weren’t disappointing enough, another study published this month found that soy, a popular alternative to estrogen for relieving hot flashes related to menopause, was ineffective.

The spate of discouraging news has so upset some women participating in the Women’s Health Initiative, researchers say, that a small number have dropped out of the study to avoid taking hormones.

Most doctors acknowledge that women will not be able to make well-informed decisions on hormone therapy until the completion of the Women’s Health Initiative. Researchers have said they expect the trial’s first major results to be released sometime in 2005.

“I feel we’re at the tip of the iceberg in trying to figure out what will make a woman’s [menopausal] symptoms go away in addition to making her life better,” Blackwood says.

Adds Dr. Howard L. Judd, the principal investigator of the WHI study site at UCLA Medical Center, “We’re feeling enormous pressure.”

Many major questions remain about the effects of hormone replacement therapy. Estrogen is often recommended to women at menopause to alleviate some of its symptoms, such as hot flashes, vaginal dryness and mood swings.

It is also recommended for women at risk of osteoporosis because replacing the estrogen lost at menopause helps maintain strong bones.

“What I tell women is if you have symptoms [of menopause], there is no reason not to take hormones,” Judd says. “And, if you are at risk for osteoporosis, take hormones.”

Estrogen is also known to increase good cholesterol (high-density lipoprotein, or HDL) and reduce the bad kind (LDL) and maintain the elasticity of arterial walls. These findings have raised hopes that hormones can be used long-term to prevent heart disease.

And some small studies have hinted that estrogen may help prevent the dementia associated with Alzheimer’s.

But, so far, there is no clear, convincing evidence that estrogen prevents heart disease or Alzheimer’s disease, experts say.

Two large, randomized, controlled clinical studies--the recent ERA study and a 1998 study called the Heart and Estrogen-Progestin Replacement Study (HERS)--produced disappointing results.

“The two best sources of data [on heart disease and estrogen] are the HERS and ERA studies, and both show the same thing: no benefit,” says Dr. David Herrington, a cardiologist at Wake Forest University who presented the ERA study two weeks ago at the annual meeting of the American College of Cardiology in Anaheim. “It’s possible that estrogen could be relatively helpful in preventing heart disease while being ineffective once disease has been established.”

However, while it is strongly implied, there is no proof that estrogen helps prevent heart disease--an issue that the Women’s Health Initiative is attempting to clarify.

Meanwhile, says Herrington, women with heart disease should use cholesterol-lowering medications and other proven remedies for controlling heart disease instead of pinning their hopes on estrogen.

As for Alzheimer’s disease and the effect of hormones, some important questions also remain unanswered. For instance, researchers do not know if long-term estrogen use can help women with dementia regain some cognitive function; the recent study from USC looked only at very short-term use.

There is also no proof that estrogen can prevent or delay the onset of Alzheimer’s disease, although some laboratory work has indicated this may be possible.

Another major area of fierce controversy is how hormone use affects cancer risk.

What is clearly known is that a woman whose uterus has not been removed during a hysterectomy has a greatly increased risk of developing uterine cancer if she takes estrogen alone. Adding the hormone progesterone to the regimen, however, offsets that risk.

That’s about all anyone agrees on when it comes to hormone therapy and cancer.

Over the last two decades, epidemiological studies on hormone use and breast cancer have produced a mixed bag of results. Some studies have found no increased risk, while others have found a small increased risk.

The recent studies from the National Cancer Institute and USC found a small increased risk, but one that accumulates over time.

The USC study found that women on both estrogen and progesterone--called combination therapy--had a higher increased risk of breast cancer than women who took estrogen alone. The authors projected that breast cancer risk rises 24% for every five years a woman takes both estrogen and progesterone, contrasted with a 6% rise per five years of estrogen-only use.

What all of this means is hotly debated.

“We’ve been worrying about progestins for more than 15 years, and this added a little, teeny bit to this,” Judd says. “But these are epidemiological studies. Most of us feel it is not a particularly sharp instrument that can weed out and clear up issues.”

However, the coauthor of the USC study, Dr. Ronald K. Ross, says that his study raises questions about the role of progesterone when used in estrogen therapy.

“I think there is still reasonably good evidence that estrogen might have fairly important health benefits,” Ross says. “Because combination therapy is fairly recent therapy, and epidemiological studies take longer to conduct, it’s not surprising that we are only now beginning to understand what progestins do to the risk-benefit equation. The emphasis has been on estrogen. But progestins obviously have an important role.”

Critics of the two recent breast cancer studies point out that the relative risk increase is small and that the accumulated risk over many years is just a projection.

“When you are dealing with small risk estimates, there are questions about whether these effects are really [caused by the hormones],” Ross says. “But let’s not bury our heads in the sand and ignore these findings. There are lots of reasons to believe these findings are real.”

Another growing area of concern about progesterone is whether adding it to the replacement regimen will affect heart disease protection, Ross says.

“The epidemiological data are overwhelming that estrogen prevents heart diseases,” he says. “The big question is, will combination therapy provide as much protection from cardiovascular disease as estrogen therapy? No one has any data on that.”

Many women have hoped to skirt the confusing questions about progesterone by using so-called “natural” progesterone. Synthetic progesterones are known as progestins and include the drug Provera. “Natural” progesterones, which are derived from yams and come in pill form, vaginal gels or topical creams, may produce different side effects and different effects on cholesterol.

But there is virtually no strong scientific data to show that “natural” progesterone products will affect heart disease or breast cancer rates, experts say.

“Natural progesterone hasn’t been studied as well as synthetic progesterone,” says Dr. Donnica Moore, a gynecologist and expert in hormone therapy in Neshanio Station, N.J. While the substance may be absorbed better, there is little other scientific data on its effects, she says.

One facet of the Women’s Health Initiative involves 27,000 women enrolled in a nine-year study examining hormones and breast cancer. But the issue is so complex that even the WHI may not offer firm answers, Judd says.

“There is a chance that the breast cancer issue will not be answerable by the WHI because the study may not be long enough,” he says. Breast cancer is usually a slow-growing disease, and too few cases may accumulate to draw conclusions.

And, Ross says, the study will also not answer whether there is a difference in estrogen versus combination-therapy protection.

While it’s far from satisfactory, a woman who cannot wait five or 10 years to decide whether to take hormones can make the best choice by discussing her history with her physician.

The discussion should cover such areas as family history of all types of cancers, heart disease and osteoporosis; personal history of benign breast disease; personal use of any hormones, including infertility treatments; date of first and last periods; and information on diet, exercise and smoking habits.

Doctors can also use a computerized model that can estimate a woman’s risk of developing a particular disease based on her health history, age and other factors.

And, until the completion of the Women’s Health Initiative, women need to realize that any decision they make will be based on a platform of information that is only partially constructed.

“With any medication, there are both risks and benefits for taking them,” Ross notes. “With hormone replacement therapy, it turns out that the equation is a very complex one.”

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The Facts and the Lingering Questions

Only some of the information that post-menopausal women need to make well-informed decisions on hormone replacement therapy is available. Much remains unknown.

There is general agreement among medical experts that estrogen therapy has the following effects:

* Usually alleviates some of the symptoms of menopause, such as hot flashes and vaginal dryness.

* Helps maintain bone health and reduce the risk of fractures.

* Increases the risk of uterine cancer if not combined with progesterone.

* Improves levels of good cholesterol.

Experts generally agree that there is a significant--although not conclusive--body of scientific evidence supporting these effects:

* Helps to prevent or delay heart disease in at least some women.

* Unsuccessful at slowing heart disease among women with established disease.

Many outstanding questions about the effects of hormones remain unanswerable because of insufficient scientific evidence or disagreement among experts over how to interpret available evidence:

* Whether hormone therapy increases the risk of breast cancer in some or all women.

* Whether adding progesterone changes the rate of protection against heart disease or changes breast cancer risk rates.

* Any effect on the development of colon and ovarian cancer.

* Whether hormone therapy improves cognitive function in women with Alzheimer’s disease; also, whether it helps prevent or delay the onset of Alzheimer’s.

What Kind of Study Is It?

Large, randomized, controlled clinical studies, in which subjects are divided into groups and followed over time, are the most scientifically rigorous of all research methods. The results of these studies are considered more reliable than those of epidemiological studies, in which researchers typically question people about their past health practices and medical histories, relying on their memory of those events. The two recent studies on breast cancer risk and hormone use were epidemiological studies.