A Cloud of Confusion Lingers Over Hormone Therapy Use
by Sherry Marts, Ph.D.
(Society for Women's Health Research, February 23, 2006 ): Hormone therapy
(HT) is often prescribed for women going through menopause to relieve the
uncomfortable symptoms of hot flashes and night sweats, as well as to prevent
osteoporosis. Before 2002, observational studies comparing women who used
HT to women who did not indicated that HT could lower the incidence of cardiovascular
disease in postmenopausal women. In search of better answers to this and related
questions, the National Institutes of Health launched the Women's Health Initiative
(WHI) in 1991. It was an ambitious 15-year research program, including a set
of clinical trials to test the effects of postmenopausal hormone therapy on
heart disease, fractures, and breast and colorectal cancer.
"Randomized, controlled clinical trials are
the most rigorous and reliable research tests available," said Phyllis Greenberger,
president and CEO of the Society for Women's Health Research in Washington,
D.C. "When you give one group of research subjects the same specific treatment
and another group of research subjects a placebo, which is an inactive substance
containing no medication, you can determine more precisely the effectiveness
of the treatment."
In contrast, observational studies merely
document an individual's health or progress by asking questions and sometimes
inviting them to participate in a clinical examination, Greenberger said.
Researchers in an observational study do not intervene or interfere in a patient's
care by mandating that they follow a specific course of action. They only
note the patient's reported activities and outcomes.
The WHI included two studies of HT. Both
were large, randomized, placebo-controlled clinical trials. One trial examined
a combination pill containing estrogens and progestin, which is a synthetic
form of the hormone progesterone. The second trial included women who had
had a hysterectomy, and compared the same estrogen preparation without progesterone
At the start of the estrogen-plus-progestin
trial, concerns were raised that the women given the inactive placebo would
be at a higher risk for developing cardiovascular disease than the women given
active hormones or that women taking hormones would be at higher risk for
developing breast cancer than those taking placebo. As a result, the researchers
agreed to stop the study if differences between the treatment and control
groups reached a predetermined threshold on these or other serious health
In 2002, three years before the study was
complete, the threshold for increased incidence of breast cancer in the treatment
group compared to the control group was reached. Investigators stopped the
study because they found that "overall health risks of coronary heart disease
events, strokes, and breast cancer exceed the benefits of the treatment, which
include lower rates of fractures and reduced risk of colon cancer."
In 2004, the estrogen-only study was stopped
when researchers found that the increased risk of stroke and blood clots exceeded
the benefits of treatment.
The decision to stop the estrogen-plus-progestin
study received a great deal of attention from the news media, women, and health
care providers. Media coverage offered messages that ranged from "hormone
therapy isn't as helpful as we thought" to "hormone therapy is dangerous for
women." Women who were taking HT feared for their health and overwhelmed their
health care providers with calls, emails, and office visits asking for help
in deciding what to do. Health care providers were often as confused as their
In response to the results of this and other
HT trials, the Food and Drug Administration (FDA) added a warning to the label
to all HT products for women stating that HT should be taken at the lowest
effective dose for the shortest time and only for relief of menopausal symptoms
and prevention of bone loss.
Gradually the attention given to the initial
announcement decreased. Researchers, health care providers, and women's health
advocates continued analyzing the results, which has led to more complete
and rational conclusions about the risks and benefits of HT.
Among the issues raised in subsequent discussion
of the WHI results were the following:
- An individual woman's risk for heart disease
or breast cancer was very low.
- All of the women in the study were significantly
past menopause. The average age of menopause in the US is 51. Only one-third
of the women in the study were between the ages of 50-59. The average age
of women in the WHI was 63. Most women who use HT are under 60, and most
start taking hormones early in the menopausal transition.
- The estrogen plus progesterone trial was
stopped because of an apparent increased risk of breast cancer in women
taking HT, but the estrogen only study did not show an increase in
risk of breast cancer in women taking estrogen alone. More analysis on HT's
impact on breast cancer will soon be published.
- The average age of the WHI participants
was 63 years old and many of them had at least one other risk factor for
cardiovascular disease, so it is likely that many of the participants had
already developed some vascular damage before taking hormones. Therefore,
the WHI study did not answer the question of whether taking hormones before
vascular disease develops can prevent it from developing.
- An increased risk of blood clots and stroke
in response to estrogen has been recognized and was part of the information
provided to prescribers well before the WHI studies were begun.
- The studies looked at only one type of
estrogen and one progesterone drug - both high-dose regimens delivered via
a pill. Since then, many forms of estrogen and natural and synthetic progesterone
have been approved by the FDA. The choice of products allows women and their
health care providers to carefully tailor the treatment to the individual
Unfortunately, the WHI did not provide the
most complete answers to questions about HT because of how the study was designed
and the health of the study's participants.
"One could argue that the study population,
described by WHI as 'generally healthy postmenopausal women,' was in fact
anything but," said Dr. Wulf Utian, M.D., Ph.D., executive director of the
North American Menopause Society. Utian points out that 40 percent of the
study's participants had high blood pressure, more than seven percent had
diabetes, 15 percent had high cholesterol, and just over three percent had
previously suffered a heart attack. These pre-existing conditions could have
had an impact on the study's results.
Other research on HT is continuing in new
clinical trials comparing low doses of hormones and various delivery systems
(pills, creams, patches) to placebo. More studies of HT are planned or ongoing,
and the results should further clarify the appropriate role of HT in symptom
relief and in prevention of disease.
Additional reports from the WHI are also
being published, including one in the Feb. 14, 2006 issue of The Archives
of Internal Medicine. It suggests that taking estrogen alone does not
increase the risk of heart disease in women who have had a hysterectomy. In
women age 50-59, when the investigators compared the total occurrence of heart
attack, bypass surgery, angioplasty and treatment for angina, the women receiving
estrogen were less likely to need treatment than those receiving a placebo.
These results only apply to women who have
had hysterectomies, which is important to note because women who have had
a hysterectomy receive estrogen without progesterone. Further research is
needed to better understand the risks and benefits of beginning HT early in
So how should women view the evidence collected
The results so far indicate that HT should
not be prescribed for the single and specific purpose of protecting against
heart disease. Some observers believe that emerging, further analysis of the
WHI indicates that the overall risks do not outweigh the benefits for all
"In my own opinion," Utian said, "these results
should be extraordinarily reassuring for average aged symptomatic women considering"
starting HT before the age of 60.
The choice to use HT should not be made without careful consideration. Women
who experience menopausal symptoms such as hot flushes, night sweats or vaginal
dryness, or who are at risk of osteoporosis, should consult their health care
providers, weigh the evidence, evaluate the advantages and disadvantages and
make informed decisions.
The Society for Women's
Health Research is the nation's only not-for-profit organization
whose sole mission is to improve the health of women through research. Founded
in 1990, the Society brought to national attention the need for the appropriate
inclusion of women in major medical research studies and the resulting need
for more information about conditions affecting women. The Society advocates
increased funding for research on women's health, encourages the study of
sex differences that may affect the prevention, diagnosis and treatment of
disease, and promotes the inclusion of women in medical research studies.
Dr. Donnica Moore has been a member of the Society since 1990 and is a past
member of its Board of Directors.
Created: 2/23/2006  - Sherry Marts, Ph.D.