The Lehman Brothers BUY rec is old news as is the information on estrogen replacement therapy. However, the NY Times is running a special on women's health and here's what they have to say about ERT:
Estrogen Replacement Therapy
Estrogen replacement therapy (ERT) is the administration of
the hormone estrogen, sometimes together with progestin, to
replace hormones no longer produced by the ovaries.
Historically, ERT (also called hormone replacement therapy,
or HRT) was given on a short-term basis to relieve the
symptoms of menopause. The trend today, however, is to
give long-term ERT for the purpose of preventing
osteoporosis and heart disease, conditions that are
increasingly likely to develop in women after menopause.
Before menopause, estrogen is secreted in large quantities
by the ovaries, and in smaller quantities by the adrenal
glands, which sit atop the kidneys. In addition, fatty
(adipose) tissue converts some of the androgens (virilizing
hormones) produced by the adrenals into estrogen. As
menopause approaches, estrogen production by the ovaries
tapers off, affecting many different tissues in the body,
including the reproductive system, urinary tract, heart, blood
vessels, bones, breasts, skin, and parts of the brain. Starting
ERT at the time of menopause can reduce many of the
negative effects of these changes. And because the changes
occur gradually, even women who have delayed therapy for
up to 10 or 15 years beyond menopause can still reap many
of these benefits. If a woman reaches her late 60s or so,
however, and shows no signs of either osteoporosis or heart
disease, there is generally no reason to begin ERT.
At present, only between 15 and 20 percent of women past
menopause are taking ERT. Part of the explanation is that
the vast majority of women pass through menopause
without experiencing any major discomforts, and, perhaps
unaware of potential heart or bone problems, they may
never seek medical care. Social and economic factors, too,
keep some women from obtaining ERT. Finally, many
doctors are not tuned in to the need to discuss ERT with
menopausal women unless they have obvious menopausal
symptoms.
At the same time, many women well aware of ERT's
potential benefits--and able to afford them--have made a
conscious choice to forgo this treatment. Some dislike the
idea of ERT on principle, questioning the wisdom of
interfering in a natural process, citing past dangers
associated with other hormone therapies (such as DES), or
rejecting the idea of treating menopause as a
hormone-deficiency disease. Other women recoil from ERT
because of a deep-seated fear of breast cancer and other
malignancies, the risks of which are slightly elevated in
women who take estrogen replacement therapy.
At present, the evidence justifying or negating these
concerns is still limited. Data will be forthcoming from the
Women's Health Initiative, a large-scale
government-sponsored study that aims, among other things,
to determine just who will benefit from ERT and under what
conditions. This same study, which will not be complete until
the year 2007, is also examining the role of other factors,
such as nutrition and exercise, in preventing health problems
in women.
Meanwhile, pharmaceutical companies are scurrying to
develop new formulations of estrogens and progestins,
including skin creams and implants (some of which are
already available in Europe), which they hope will prove to
be safer than current options but just as beneficial. In the
meantime, the individual woman is left to make what can be
a confusing choice in the face of incomplete information. For
anyone considering ERT, it is important to have a thorough
discussion with a clinician about the pros and cons. Most
clinicians are advocates of ERT because of the potential
benefit of preventing cardiovascular disease.
How is ERT administered?
The most commonly prescribed ERT in the United States
includes mixtures of several forms of estrogen taken from
the urine of pregnant mares. Called conjugated estrogens,
these preparations are sold under trade names such as
Premarin. Natural forms of estrogen (manufactured in the
laboratory), which are less potent than conjugated
estrogens, are also sometimes used--estradiol (Estrace and
Estraderm), estropipate (Ogen), and esterified estrogens
(Estratab).
ERT can be administered in the form of pills or absorbed
through the skin from transdermal patches . Because
hormones from patches (such as Estraderm) enter the bloodstream directly, they
bypass the digestive system and are not immediately processed in the liver, a place
where estrogen affects protein synthesis in both positive and negative ways. Estrogen in
the liver seems to increase the proportion of the so-called good cholesterol, HDL, but
it can also have adverse effects on the liver and may exacerbate high blood pressure.
Women who cannot use any of these systemic estrogens have the alternative of vaginal
creams, which are not generally considered a full-scale form of ERT but which can
relieve symptoms of vaginal atrophy--the drying and thinning of tissues in the vaginal
wall. Many of these creams contain conjugated estrogens (Premarin). Usually women
are instructed to use half to 1 applicator daily for 3 weeks, after which time just half an
applicator once or twice weekly usually suffices. Since some of the estrogen in vaginal
creams is absorbed into the bloodstream, more frequent use begins to incur the same
risks as oral estrogens.
Because the estrogen used for ERT is about 10 times less powerful than the estrogen
used in oral contraceptives, the risks and benefits associated with birth control pills
cannot necessarily be extended to ERT. In fact, several of the more serious risks and
complications once associated with ERT were based on doses of estrogen much higher
than are now generally prescribed. Daily doses of conjugated estrogen were once as
high as 1.25 to 2.5 milligrams; today the standard dose is only 0.625 mg. Usually taken
daily, this dosage seems to confer the same protective effects as higher doses which
are more likely to overstimulate breast and uterine tissues.
Since the 1970s researchers have known that supplementary estrogen when taken by
itself . This increased risk can be virtually eliminated, however, when estrogens are
taken in combination with progestins. These are synthetic compounds that behave
much like the hormone progesterone, and most of them have mild androgenic
(virilizing) properties. In contrast to the progestins used in oral contraceptives--which
tend to have the strongest virilizing properties--the most common form of progestin
used in ERT, medroxyprogesterone acetate (Provera or Cycrin), is substantially less
potent.
What are the benefits of ERT?
There is no question that ERT is greatly effective in easing many of the symptoms of
menopause. Not only does it eliminate hot flashes and reverse vaginal atrophy and
associated changes within weeks, but it can even help sagging pelvic muscles. There is
also fairly good evidence that daily estrogen treatment can improve mood in women
who are mildly depressed, although it sometimes makes matters worse for women who
are already suffering from clinical depression. It has no proven effect on the aging of
skin or hair loss.
Preventing osteoporosis
Even more impressive is the well-established ability of ERT to slow the bone loss
associated with osteoporosis. Osteoporosis . Estrogen taken in low doses of 0.625
milligrams daily has a beneficial effect on bone, by improving calcium absorption and
retarding bone loss.
Estrogen is most effective for preventing osteoporosis when it is started in the first 5
years after menopause, a time when bone loss is fastest. It is also beneficial, however,
even when it is started many years after menopause or in women with long-standing
osteoporosis. Although estrogen must be taken for at least 7 years to have a long-term
benefit, its ability to prevent the development of osteoporosis continues for as long as it
is taken. There is even some evidence that progestins taken along with the estrogen
have a synergistic effect in slowing bone loss.
It is still not clear whether estrogen taken through a transdermal patch is equally
effective in preventing osteoporosis, although so far no differences have appeared
between women who use the pill or the patch.
Preventing heart disease
Estrogen therapy has the potential to reduce greatly a woman's risk of developing and
dying from heart disease, particularly from coronary artery disease. A number of
studies show that taking estrogen after menopause can decrease the incidence of
certain risk factors associated with heart disease and can also substantially lower the
death rate from heart attacks. One of the most commonly cited of these studies, the
Nurses' Health Study, conducted by researchers at the Brigham and Women's
Hospital and the Harvard Medical School in Boston, involved 48,470 postmenopausal
nurses, who were followed for 10 years. Of these women, those who took estrogen
had a heart attack rate almost half that of the women who took no replacement
therapy.
A drawback to this and most of the other studies is that the women who were taking
ERT may also have had a higher standard of living and been inclined to take better
care of their health in general, factors that may have made them less vulnerable to heart
attacks, with or without ERT. In an ideal study similar groups of women would be
randomly selected to take, or not take, ERT and then would be compared years later
to see which group had more heart attacks. In the Nurses' Study and similar research,
women made their own choice about whether to take the drug, and this nonrandom
factor may have skewed the results.
Virtually all of the studies thus far have looked at the effects of estrogen replacement
alone, and this has led some researchers to fear that these benefits may be countered
to some degree by the addition of progestins, which only recently became a routine
part of most ERT. Whereas estrogen tends to improve the relative ratio of HDL
cholesterol to LDL cholesterol--which, in turn, is associated with a lowered risk of
coronary artery disease--progestins tend to lower this ratio in favor of LDL
cholesterol. Recent studies suggest, however, that these fears about progestin may be
unwarranted. Also encouraging is the observation that medroxyprogesterone acetate,
the progestin most commonly used in ERT, has less of a negative impact on the ratio of
HDL to LDL than do progestins derived from testosterone. Natural progesterone
seems to have even less of an effect, but oral preparations of natural progesterone are
not commonly prescribed in the United States and may be difficult to obtain locally. In
any case, the beneficial effects of estrogen on the cardiovascular system are only partly
due to their effects on lipids.
In short, the final word still is not in on the effect of various hormone regimes on the
risk of heart disease. The results of the Women's Health Initiative (still years away)
may provide some of these answers.
What are the risks and complications?
Hypertension, stroke, and migraine
In the past, women with these conditions were thought to be at higher risk for
complications from ERT. Researchers think that these high-risk groups may actually
receive the most benefit from supplemental estrogen. Replacement doses of estrogen
apparently have little effect on blood pressure and seem to be safe even in women with
mild hypertension. Nor does ERT appear to alter a woman's lifetime risk of stroke.
As for the association between ERT and migraine headaches, the jury is still out. There
is evidence linking both estrogens and progestins to migraines, plus some circumstantial
evidence indicating that these hormones probably have something to do with who gets
headaches and when. Even so, while some women find that ERT exacerbates their
headaches, just as many others find that it provides relief or no change at all. The best
strategy is probably a little personal experimentation, with the understanding that if one
hormone regimen makes migraines worse, it might be worth trying another one (such as
a lower dose of estrogen or a transdermal patch) before abandoning the idea of ERT
altogether.
Endometrial cancer
In women who still have a uterus, there seems to be no significant increase in
endometrial cancer from ERT when estrogen is supplemented with progestins. For this
reason progestins are now a routine part of ERT, except in women who no longer have
a uterus (in which case endometrial changes are impossible). In women who have had
hysterectomy, clinicians usually recommend unopposed estrogen.
Adding progestins to ERT has its own set of disadvantages. In addition to their
potential for decreasing estrogen's positive benefits to the heart, progestins can
sometimes produce transient bloating, breast tenderness, irritability, and (in higher
doses) depressed mood. More distressing to many women is the resumption of
monthly menstrual bleeding. The traditional way in which clinicians prescribe ERT
includes low doses of medroxyprogesterone (Provera) taken for about 12 days each
month. In 85 to 90 percent of women on this regime, monthly withdrawal bleeding
begins as soon as the Provera is stopped. Monthly bleeding usually continues for a
number of years after ERT is begun, but as the uterus ages, the bleeding eventually
ceases.
Because many women are unwilling to tolerate having "periods" again after menopause,
increasing numbers of clinicians are prescribing progestins on a continuous daily basis.
In the United States, this usually involves taking 0.625 mg of conjugated estrogen along
with 2.5 mg of medroxyprogesterone acetate each day. But even this regime can lead
to irregular spotting or bleeding in 30 to 50 percent of women for the first 6 months
(this seems to be less of a problem in women well past menopause). Since abnormal
spotting can be a symptom of uterine tissue abnormalities, such as hyperplasia or
cancer, it can be difficult for a clinician to know whether to recommend an endometrial
biopsy or "watchful waiting."
Breast cancer
Although many studies in the past decade have attempted to document an association
between breast cancer and ERT, the results are still inconclusive. One recent
meta-analysis, which pooled and synthesized many smaller studies, found absolutely no
increased risk for breast cancer in postmenopausal women who took long-term
estrogen. But another meta-analysis found that the relative risk of breast cancer was
about 30 percent higher in women on ERT--although the risk was limited to women
who used estrogen for more than 15 years and was particularly high for women with a
family history of breast cancer. For a 50-year-old woman, this translates roughly into
an increase in lifetime risk from 10 to 13 percent.
The Nurses' Health Study has shown that the risk of breast cancer in women who use
estrogen alone is similar to that when estrogen is combined with progestins. In this
large-scale study cancer risk was found to increase by about 40 percent in women
who used estrogen (with or without progestins) for 5 years or more. Deaths from
breast cancer showed a similar increase. Other studies have shown, however, that the
cancers which developed in women using ERT seemed to be slower-growing and
more curable than other breast cancers--perhaps because ERT-associated cancers are
biologically different.
In short, the relationship between ERT and breast cancer is unresolved. Although it is
possible that estrogen use for more than 5 years may be linked to an increase in breast
cancer risk, there simply have not been enough women on ERT long enough to answer
this question definitively. Investigators will continue to address this issue as long-term
ERT becomes more common.
Gallstones and blood clots
ERT seems to put women at slightly increased risk of developing gallstones, probably
because estrogen stimulates the liver to increase the amount of cholesterol in the bile.
Using progestins in conjunction with estrogen does not seem to affect this risk.
Although high doses of estrogen have been associated with blood clotting, these
problems do not appear to occur at the low doses now used for ERT. They are even
less likely--as are gallstones--when ERT is taken via transdermal patches.
An individual decision
Given the limited information that is currently available, ERT still seems like a good bet
for most women after menopause. In fact, the growing consensus in the medical world
is that estrogen therapy--continued for one or even two decades--enhances the quality
of life and even prolongs life for most women. This is largely because the risk of
developing and dying from heart disease is so high in women past 50. Lowering this
risk even a bit, say advocates of ERT, can have huge repercussions in terms of saving
lives and preserving the quality of life, despite the other risks. For the average
postmenopausal woman, death from heart disease is 4 to 5 times more common than
deaths from breast and endometrial cancer combined.
For most women, it boils down to this: after age 50 the risk of developing coronary
artery disease is about 45 percent, and the risk of dying from heart disease is about 30
percent. In addition, the risk of incurring an osteoporosis-related fracture is 40 percent.
Taking estrogen seems to decrease these risks substantially, and when it is combined
with progestins, ERT does not significantly increase the risk of endometrial cancer. In
contrast, there is the possibility that ERT may increase the risk of developing breast
cancer from about 10 percent to about 13 percent. As for gallstones, most clinicians
feel that the slight increase associated with ERT has only negligible effects on a
woman's overall health and longevity. All of this makes ERT sound quite appealing for
the average woman.
But of course no one is average. Each individual has her own risk of developing heart
disease or breast cancer, based on her own health and family history, as well as other
risk factors. In addition, many of the judgments about the advisability of ERT are
based on health risks for white women--and these may not apply to women of other
races and backgrounds. Also, some women may find that they experience intolerable
side effects when they use various forms of ERT.
For all of these reasons, each woman must consider her personal situation--not to
mention her individual feelings about quality of life--and discuss these matters with her
clinician before making a decision about ERT.
There are some women for whom ERT may simply be inappropriate. These include
women who have had breast or uterine cancer or who currently have active liver
disease. Women who have histories of stroke, heart attacks, and circulatory disorders
involving blood clots have also traditionally been counseled against ERT, but many
clinicians now feel that ERT is reasonable for these women so long as the problems
were not related to high levels of estrogen (such as may have occurred during oral
contraceptive use or pregnancy). For women who are at particularly high risk for
coronary artery disease, such as smokers and women with hypertension or diabetes,
the benefits of estrogen replacement far outweigh the risk. Women with high levels of
triglycerides in the blood or very high blood pressure should also weigh the pros and
cons carefully with their physicians. These women need closer monitoring after starting
ERT to be sure it does not exacerbate the underlying condition.
Finally, whatever her personal risk factors, every woman who is using ERT should
have an annual pelvic and breast examination. She should also have a mammogram
done when therapy is initiated and then at yearly intervals thereafter. Women on
unopposed estrogens who still have a uterus (for example, women who for whatever
reason cannot tolerate the side effects of progestins) need to have yearly endometrial
biopsies to check for cancerous or precancerous changes. These women may
sometimes experience abnormal vaginal bleeding, including withdrawal bleeding (on the
days when the estrogen is not taken) and irregular bleeding--which may but does not
necessarily indicate an endometrial problem. Regular endometrial biopsies are generally
unnecessary for women using combinations of estrogens and progestins unless they
experience heavy, irregular, or prolonged bleeding (more than a normal menstrual
period). |
