- What is menopause?
Menopause is the time in a woman’s life when menstruation (having
a period) ends. It is part of a biological process that begins, for most women,
in their mid-thirties. During this time, the ovaries gradually produce lower
levels of natural sex hormones—estrogen and progesterone. Estrogen promotes
the normal development of a woman’s breasts and uterus, controls the
cycle of ovulation (when an ovary releases an egg into a fallopian tube),
and affects many aspects of a woman’s physical and emotional health.
Progesterone controls menstruation and prepares the lining of the uterus to
receive the fertilized egg.
“Natural menopause” occurs when a woman has her last menstrual
period, or stops menstruating, and is considered complete when menstruation
has stopped for 1 year. This usually occurs between ages 45 and 55, with variations
in timing from woman to woman. Women who undergo surgery to remove both ovaries
(an operation called bilateral oophorectomy) experience “surgical menopause”—an
immediate end to menstruation caused by lack of hormones produced by the ovaries.
By the time a woman has reached natural menopause, estrogen output has decreased
significantly. Even though low levels of this hormone are produced by other
organs after menopause, these levels are only about one-tenth of the level
found in premenopausal women. Progesterone is nearly absent in menopausal
women.
- What are menopausal hormones and why are they
used?
Doctors may recommend menopausal hormones to counter some of the problems
often associated with the onset of menopause (hot flashes, night sweats, sleeplessness,
and vaginal dryness) or to prevent some long-term conditions that are more
common in postmenopausal women, such as osteoporosis (a condition characterized
by a decrease in bone mass and density, causing bones to become fragile).
Menopausal hormone use (sometimes referred to as hormone replacement therapy
or postmenopausal hormone use) usually involves treatment with either estrogen
alone or estrogen in combination with progesterone or progestin, a synthetic
hormone with effects similar to those of progesterone. Among women who are
prescribed menopausal hormones, women who have undergone a hysterectomy (surgery
to remove the uterus and, sometimes, the cervix) are generally given estrogen
alone. Women who have not undergone this surgery are given estrogen plus progestin,
which is known to have a lower risk of causing endometrial cancer (cancer
of the lining of the uterus).
- How does medical research determine the benefits and risks
of taking menopausal hormones?
Researchers commonly conduct two very different, yet important types of
studies with people to examine the benefits and risks of hormone use: clinical
trials and observational studies. In clinical trials, the participants are
given either hormones or placebos (look-alike pills that do not contain any
drug) to determine the effect of the hormones on various conditions and diseases.
In observational studies, the investigators do not try to affect the outcome;
they compare the health status of women taking hormones to that of women not
taking hormones.
- What has medical research found out about the risks
and benefits of hormone use after menopause?
The most comprehensive evidence about the risks and benefits of taking hormones
after menopause to prevent disease comes from the Women’s Health Initiative
(WHI) Hormone Program, which was sponsored by the National Heart, Lung, and
Blood Institute (NHLBI) and the National Cancer Institute (NCI), parts of
the National Institutes of Health (NIH). This research program examined the
effects of menopausal hormones on women’s health. The WHI Hormone Program
involved two studies—the use of estrogen plus progestin for women with
a uterus (the Estrogen-plus-Progestin Study), and the use of estrogen alone
for women without a uterus (the Estrogen-Alone Study). In both hormone therapy
studies, women were randomly assigned to receive either the hormone medication
being studied or the placebo.
The WHI Estrogen-plus-Progestin Study was stopped in July 2002, when investigators
reported that the overall risks of estrogen plus progestin, specifically Prempro™,
outweighed the benefits (1). The researchers found that
use of this estrogen-plus-progestin pill increased the risk of breast cancer,
heart disease, stroke, blood clots, and urinary incontinence. However, the
risk of colorectal cancer and hip fractures was lower among women using estrogen
plus progestin than among those taking the placebo (1).
In addition, the WHI Memory Study showed that estrogen plus progestin doubled
the risk for developing dementia (a decline in mental ability in which the
patient can no longer function independently on a day-to-day basis) in postmenopausal
women age 65 and older. The risk increased for all types of dementia, including
Alzheimer’s disease (2).
The WHI Estrogen-Alone Study, which involved Premarin™, was stopped
in February 2004, when the researchers concluded that estrogen alone increased
the risk of stroke and blood clots. In contrast with the WHI Estrogen-plus-Progestin
Study, the risk of breast cancer was decreased in women using estrogen alone
compared with those taking the placebo (see Question 5).
Use of estrogen alone did not increase or decrease the risk of colorectal
cancer (3). Similar to the results seen in the Estrogen-plus-Progestin
Study, women using estrogen alone had an increased risk of urinary incontinence
and a decreased risk of hip fractures.
Another large epidemiologic study, the Million Women Study, enrolled 1.3
million women in the United Kingdom. This study evaluated health outcomes
in women using and not using menopausal hormones. Several analyses have been
published to date, and many more are expected in the future (4,
5, 6).
- How does menopausal hormone use affect breast
cancer risk and survival?
The WHI Estrogen-plus-Progestin Study concluded that estrogen plus progestin
increases the risk of invasive breast cancer. After 5 years of follow-up,
women taking these hormones had a 24 percent increase in breast cancer risk
compared with women taking the placebo. The increase amounted to an additional
8 cases of breast cancer for every 10,000 women taking estrogen plus progestin
for 1 year compared with 10,000 women taking the placebo (7).
A detailed analysis of data from the WHI Estrogen-plus-Progestin Study showed
that, among women taking estrogen plus progestin, the breast cancers were
slightly larger and diagnosed at more advanced stages compared with breast
cancers in women taking the placebo. Among women taking estrogen plus progestin,
25.4 percent of the cancers had spread outside the breast to nearby organs
or lymph nodes compared with 16.0 percent among nonusers. Women taking estrogen
plus progestin also had more abnormal mammograms (breast x-rays that require
additional evaluation) than the women taking the placebo (7).
The WHI Estrogen-Alone Study concluded that taking estrogen did not increase
the risk of breast cancer in women with a prior hysterectomy, at least for
the 7 years of follow-up in the study. Further analysis of data from the study
indicated a 20 percent decrease in risk of breast cancer in women taking estrogen
alone, although this decrease was seen mainly in the occurrence of early-stage
breast cancer and ductal
breast cancer (a specific type that begins in the lining of the milk ducts
in the breast) (8). The observed
reduction amounted to 6 fewer cases of breast cancer for every 10,000 women
taking estrogen for 1 year compared with 10,000 nonusers, but this lower incidence
was not statistically
significant; i.e., the lower incidence could have arisen by chance rather
than being related to estrogen-alone use (8). The Estrogen-Alone
Study also showed a substantial increase in the frequency of abnormal mammograms
(8).
A comprehensive review of data from 51 epidemiological (population) studies
published in the 1980s and 1990s found a statistically significant increase
in breast cancer risk among current or recent users of any hormone replacement
therapy compared with the risk among nonusers. Most women in the analysis
(88 percent) had used estrogen alone, and data for estrogen-plus-progestin
users was not analyzed separately. Analysis of the pooled data also showed
that the risk of breast cancer increased with increasing duration of hormone
use, and this effect was more prominent in women with low body weight or a
low body mass index. However, breast cancers in hormone users were less likely
to have spread to other parts of the body compared with the breast cancers
in nonusers. The increase in breast cancer risk largely, if not completely,
disappeared about 5 years after cessation of hormone use (9).
As part of the Million Women Study, researchers examined six types of breast
cancer among users and nonusers of menopausal hormones. The results showed
that the effects of hormone use varied among breast cancer types. Overall,
breast cancer risk was significantly increased among current users, although
the risk was lower among women with higher body mass index (5).
- What are the effects of hormone use on the risk of endometrial
cancer?
Studies have shown that long-term exposure of the uterus to estrogen alone
increases a woman’s risk of endometrial cancer. The risk associated
with estrogen plus progestin appears to be much less, but some data suggest
that the risk is still increased compared with the risk for nonusers. The
long-term effects of estrogen plus progestin on endometrial cancer risk remain
uncertain (10).
The WHI Estrogen-plus-Progestin Study showed that endometrial cancer rates
for women taking estrogen plus progestin daily were the same as or possibly
less than those for women taking the placebo pill. Uterine bleeding, however,
was a common side effect, leading to more frequent biopsies and ultrasounds
for women taking estrogen plus progestin compared with those taking a placebo
(11).
The Million Women Study confirmed a lower risk of endometrial cancer in women
taking estrogen plus progestin in comparison with those taking estrogen only
or tibolone, a synthetic steroid that is not available in the United States
(6).
- How does menopausal hormone use affect the risk of ovarian
cancer?
Several observational studies have found that the use of estrogen alone is
associated with a slightly increased risk of ovarian cancer for women who
used this hormone for 10 or more years. One observational study that followed
44,241 menopausal women for approximately 20 years concluded that women who
used estrogen alone for 10 or more years were twice as likely to develop ovarian
cancer compared with women who did not use menopausal hormones (12).
Another large observational study also found an association between estrogen
use and death due to ovarian cancer. In this study, the increased risk appeared
to be limited to women who used estrogen for 10 or more years (13).
The results from the Million Women Study showed that women currently using
menopausal hormones had an increased risk of developing ovarian cancer and
a 20 percent likelihood of dying from the disease compared with nonusers.
However, the increased risk disappeared after hormone use stopped (4).
Data from the WHI Estrogen-plus-Progestin Study indicate that there may be
an increased risk of ovarian cancer with use of estrogen plus progestin (11).
After 5.6 years of follow-up, a 58 percent increased risk of ovarian cancer
was reported in women using estrogen plus progestin compared with nonusers,
but the increased risk was not statistically significant. One observational
study suggested that regimens of estrogen plus progestin do not increase the
risk of ovarian cancer if progestin is used for more than 15 days per month
(14), but this study was too small to draw firm conclusions.
More research is needed to clarify the relationship between menopausal hormone
use, particularly for estrogen plus progestin, and the risk of ovarian cancer.
- How does menopausal hormone use affect the risk
of colorectal cancer?
After 5 years of follow-up of women taking estrogen plus progestin, the WHI
Estrogen-plus-Progestin Study reported a 37 percent reduction in colorectal
cancer cases compared with women taking the placebo (1).
On average, the researchers found that if a group of 10,000 women takes estrogen
plus progestin for a year, 6 fewer cases of colon cancer will occur than in
a group of nonusers. These findings are consistent with observational studies,
which have suggested that the use of postmenopausal hormones may reduce the
risk of colorectal cancer (1, 15). The
WHI Estrogen-Alone Study concluded that estrogen alone had no significant
effect on colorectal cancer risk (3).
- Should women with a history of cancer take menopausal
hormones?
One of the roles of naturally occurring estrogen is to promote the normal
growth of cells in the breast and uterus. For this reason, it is generally
believed that menopausal estrogen use by women who have already been diagnosed
with breast cancer may promote further tumor growth. Studies of hormone use
to treat menopausal symptoms in breast cancer survivors have produced conflicting
results.
In one trial, 434 breast cancer survivors receiving either estrogen alone
or estrogen plus progestin were followed for 2 years before the study was
stopped because researchers concluded that even short-term use of hormone
replacement therapy posed an unacceptable risk of breast cancer recurrence.
Among these study participants, 26 women in the group receiving hormone replacement
therapy had another occurrence of breast cancer compared with 7 women in the
group receiving no hormone replacement therapy (16). In
another study, which included 378 women who were followed for 4 years, 11
women receiving hormone replacement therapy had another occurrence of breast
cancer compared with 13 women receiving no hormone replacement therapy, so
the risk of breast cancer recurrence was not increased (17).
A review of 15 studies comprising a total of 1,416 breast cancer survivors
and 1,998 women without a history of breast cancer found no increase in risk
of cancer recurrence with hormone replacement therapy use (18).
There is limited research on the risks associated with menopausal hormone
use by women who have had other cancers, particularly gynecological cancers.
One review of the published research found that no firm conclusion could be
drawn about the safety of hormone use in women with a history of cancer. However,
survivors of gastric and bladder cancer and meningioma may be at higher risk
of a recurrence. Survivors of gynecological cancers may be at higher risk
because these cancers tend to be more hormone-dependent, but more studies
are needed (19).
- Does the way in which hormones are administered make
a difference?
Most of the data on the long-term health effects of hormones come from studies
in which hormones (estrogen alone or estrogen plus progestin) are administered
orally in the form of pills. Hormones in the form of transdermal patches or
gels are also used to treat menopause-related symptoms. Estrogen-containing
vaginal creams and rings can be used specifically for vaginal dryness. Progesterone
is also available as a pill or gel. The amount of estrogen that enters the
bloodstream from estrogen-containing vaginal creams and rings depends on the
types of hormones and the dose. Generally, vaginal administration of hormones
results in lower levels of circulating hormones compared with an equivalent
oral dose. Because the vaginal epithelium (thin layer of tissue that covers
the vagina) responds to very small doses of estrogen, low-dose estrogen-containing
creams or gels can be used.
- What should women do if they are concerned about taking
menopausal hormones?
Although menopausal hormones have short-term benefits such as relief from
hot flashes and vaginal dryness, several health concerns are associated with
their use. Women should discuss with their health care provider whether to
take menopausal hormones and what alternatives may be appropriate for them.
The U.S. Food and Drug Administration (FDA) currently advises women to use
menopausal hormones for the shortest time and at the lowest dose possible
to control symptoms. The FDA publication Menopause & hormones
provides additional information about the risks and benefits of hormone use
for menopausal symptoms. This resource is available at http://www.fda.gov/womens/menopause/mht-FS.html
on the Internet.
- What are the alternatives for women who choose not to
take menopausal hormones?
To decrease the risk of chronic disease, women can adopt a healthy lifestyle
by exercising regularly, eating a healthy diet, limiting the consumption of
alcohol, and not starting to smoke or, for smokers, trying to quit. Eating
foods rich in calcium and vitamin D or taking dietary supplements containing
these nutrients can help prevent osteoporosis. Results from the WHI showed
that taking calcium and vitamin D supplements provided some benefit in preserving
bone mass and preventing hip fractures, particularly in women age 60 and older.
Although generally well tolerated, these supplements were associated with
an increased risk of kidney stones. Other drugs, such as alendronate (Fosamax®),
raloxifene (Evista®), and risedronate (Actonel®), have been shown
to prevent bone loss. In addition, parathyroid hormone (Forteo®) is approved
by the FDA for osteoporosis treatment.
Short-term menopause-related problems may go away on their own and frequently
require no therapy at all. Local therapy for specific symptoms, such as vaginal
dryness and urinary bladder conditions, is available. Some women seek relief
from menopausal symptoms with nonprescription complementary and alternative
therapies containing estrogen-like compounds. Some sources of these estrogen-like
compounds include soy-based products, whole grain cereal, oilseeds (primarily
flaxseed), legumes, and the botanical black cohosh. The benefits and risks
of most of these agents have not been proven, however.
One NIH-funded study, the Herbal Alternatives (HALT) for Menopause Study,
involved 351 women, some of whom were postmenopausal while others were approaching
menopause. All of these women experienced hot flashes and night sweats and
were given herbal supplements, menopausal hormones, or no therapy. Women in
the herbal supplement groups received black cohosh alone, a multibotanical
supplement (including black cohosh), or the multibotanical supplement plus
counseling to increase their intake of dietary soy. Women in the herbal supplement
groups had no significant reduction in the number of hot flashes and night
sweats compared with women who received no therapy. The women who received
menopausal hormones had significantly fewer menopausal symptoms compared with
the women who received no therapy (20).
Women should talk with their doctor about the option best for them.
- What research still needs to be done?
Unresolved questions include whether different forms of the hormones, lower
doses, different hormones, or different methods of administration are safer
or more effective; whether risks and/or benefits persist after women stop
taking hormones; whether women might be able to take hormones safely for a
short period of time; and whether certain subgroups of women, including women
with a history of cancer, might be at higher or lower risk than the general
population.
The WHI continues to evaluate the longer-term effects of calcium and vitamin
D supplements on preserving bone mass, preventing hip fractures, and reducing
colon cancer risk, and continues long-term follow-up of women in the hormone
trials.
The NIH continues to sponsor research to evaluate the effects of estrogen-like
compounds on menopausal symptoms and long-term health after menopause. Several
NCI-sponsored studies are evaluating the effectiveness of nonhormonal treatments,
such as the botanical St. John’s wort and the antidepressant drug citalopram
hydrobromide, in reducing hot flashes in women with a history of breast cancer.
- Where can people get more information about menopausal
hormone use?
The following resources provide additional information about menopausal
hormones and the WHI:
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