question, hormone replacement therapy has become the most controversial
issue in menopausal gynecology. The following overview of this
issue was written by Anthony
A. Luciano, M.D. (one of the founding
members of the Womens' Surgery Group. You can view his CV on the
Womens' Health Initiative (WHI) Perspective
After our usual Saturday morning match, my tennis partner, Rafael,
asked if I still prescribed estrogen and progestin therapy
(EPT) for menopausal women,
given the recent WHI findings of increased cardiovascular disease,
stroke, and breast cancer associated with its use. "Of course",
I said. In fact, most
of my symptomatic postmenopausal patients continue on estrogen
or EPT to control their menopausal symptoms. In addition,
my wife Mary continues to take EPT.
Before he asked, I emphatically declared that I very much loved
my wife of almost 30 years. But I certainly understood his
concern regarding EPT. In
fact, shortly after the WHI findings became widely publicized,
my wife, like several of her friends and many of my patients,
discontinued EPT. But after
8-10 weeks of not taking hormones, just like several other symptomatic
postmenopausal women, Mary resumed therapy because of difficulty
tolerating the vasomotor
symptoms and the associated disturbances of sleep patterns, moods,
etc. Several other postmenopausal women, however, were able
to cope with the transient
recurrence of menopausal symptoms, and I was happy to encourage
them to permanently discontinue ET/EPT, since the original
reason for starting the therapy (vasomotor
symptoms) was no longer an issue and the secondary, long-term
benefits of EPT had been seriously challenged by WHI data.
Although the WHI has significantly
affected our clinical practice regarding the long-term therapy
with EPT, it has not precluded its use in symptomatic postmenopausal
women, whose distressing
symptoms and quality of life are dramaticaly improved by EPT.
Overview and implications of the WHI data
The WHI study was designed in 1991-1992 to determine the role of
long-term therapy with either unopposed estrogen (ET) or combined
estrogen and progestin
(EPT) in postmenopausal women’s health. For the evaluation of long-term
ET, the study enrolled 10,739 hysterectomized women who were randomized to
either conjugated equine estrogen (CEE), marketed as Premarin, 0.625 mg daily
or placebo. For the evaluation of long-term EPT, it enrolled 16,608 asymptomatic
women with intact uterus, aged 50 to 79 years, who were randomized to either
CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg, marketed as Prempro,
The primary focus of the trial was to quantify the reduction
in the incidence of cardiovascular disease events versus the increased
incidence of breast cancer associated with the use of ET/EPT. Secondary
benefits of EPT included the reduction of osteoporosis related fractures,
colon cancer and overall mortality, versus the increased incidence of thromboembolic
events, endometrial cancer and other adverse reactions. From these data
they would calculate total benefits
and risks and reach a final conclusion regarding the overall
safety of long term ET/ EPT use.
It is important to emphasize that the
WHI study did not evaluate the benefits of ET/EPT on vasomotor
sweats, and vaginal dryness, which are the most common reasons for their
use. The goal of the study was to determine whether or not ET/EPT
should be considered for long term use by postmenopausal
women to prevent cardiovascular
disease, stroke, fractures, colon cancer,
and overall mortality. Although the study was designed for 8-year
duration, assessment of the data was carried out semiannually by
an independent Data
Safety Monitoring Board (DSMB) to determine trends.
Results of the EPT (Estrogen + Progestrone) Arm of WHI
During the 10th interim analysis of the data from the EPT arm of
the study (May 31, 2002), the DSMB found that the adverse effects
disease originally noted during the fifth interim analysis in 1999 persisted.
Moreover, the increased incidence of breast cancer had crossed the designated
boundary and the global index. This supported a finding of overall harm for
ETP. The DSMB concluded that the evidence of harm for breast cancer, coronary
disease, stroke and thromboembolic events outweighed the evidence of benefit
for fractures and colorectal cancer. Because the overall risks of ETP
outweighed its benefits, on July 9, 2002, after an average of
5.2 years of observation, the study arm evaluating the combined
placebo was halted.
It is important to notice that the arm of the WHI study designed to examine
the use of unopposed estrogen, CEE 0.625 mg daily, was not terminated.
When the EPT arm of the study was halted, participants using the study
drug, Prempro, had an increased incidence of 26% of breast cancer,
stroke, 29% ofcoronary heart disease events, and 110% of thromboembolic
events. On the benefits side, they experienced a 37% reduction in colorectal
cancer and 34% reduction in hip fractures. But these reductions were not
sufficient to offset the increased risk. It
to point out that there was no difference in mortality rates between the
EPT and the placebo groups.
Because relative risks are confusing and often misunderstood, the
results were also reported in absolute values, expressed in the
number of additional
for treated women-years.
Thus among 10,000 women taking EPT for a year, there will be 8 more cases
breast cancer, 8 more strokes, 8 more pulmonary embolic events, and 7 more
myocardial infarctions, but 6 fewer colorectal cancers and 5 fewer hip
fractures. Although the absolute risk for an individual woman remains quite
per year), when counting all events over the 5.2 years of the trial, the
number of women experiencing a global index event was about 100 more per
taking EPT than in those taking placebo.
Extrapolating to the population
at large to a longer treatment duration, the use of EPT could account
tens of thousands additional adverse events. Because of this, the Writing
Group for the WHI concluded that EPT should not be prescribed for
the purpose of preventing cardiovascular disease, stroke, colon
cancer or fractures.
These results do not preclude prescribing EPT for the purpose
of alleviating vasomotor symptoms, night sweats, vaginal dryness and
that affect a large number of menopausal women. Indeed, the ability of
ET/EPT to relieve vasomotor symptoms remains unquestioned and unequalled
currently available medical or alternative therapies.
The WHI did not
assess vasomotor symptoms relief; in fact, women with severe hot flashes
excluded from the study. Consequently, the major benefits and the most
for prescribing EPT were not considered in the risk- benefit ratio and
in the assessment of the global index. Had this been done, and had the
symptomatic women with significant hot flashes, it is likely that the
risk-benefit ratio might have yielded different results and perhaps
conclusion. Nevertheless, the data from the WHI study does provide valuable
which allows us to discuss benefits and risks of ETP more precisely and
more objectively, especially for asymptomatic postmenopausal women.
Impact of WHI on clinical practice
Prior to the WHI results becoming public, the most common reasons
for prescribing ET/EPT
were vasomotor symptoms, night sweats, vaginal dryness and mood
swings associated with menopause. Secondary reasons for encouraging
postmenopausal women to
use EPT included the protective effects on cardiovascular disease, osteoporosis
and perhaps Alzheimer’s disease. Of course, the risks of breast
cancer and thromboembolic events
were also considered, but we believed that “they paled in comparison
to the purported benefits”. The data from the EPT arm of the WHI
study has dramatically changed the secondary reasons for prescribing
used to be considered secondary benefits of EPT (cardiovascular disease
and stroke) must now be considered additional risks of EPT, which should
discourage women from its long-term use.
Prior to the WHI data, the cardiovascular protective effect of
ET/EPT had been substantiated by several epidemiological studies,
as well as
clinical studies, which consistently reported the beneficial effects
of ET/EPT on lipid profile and directly on vessel walls in decreasing
and inducing vasodilatation. Were all these studies erroneous or
is there some reason to explain the differences in the findings
WHI study? It has been stated that observational studies have pitfall
selection bias and compliance bias. It has been repeatedly stated that
take hormones are typically healthier, better educated and wealthier
fewer coronary risk factors. Consequently, the observed favorable outcome
more their healthier status than their hormone therapy. Although these
confounding factors might have played a role in exaggerating the benefits,
it is unlikely
that they would have masked the increased risk currently observed with
the WHI and other recently published prospectively randomized studies
HERS 4 and WEST 5 studies). Moreover, the other benefits (osteoporosis
and colon cancer protection) and risks (thromboembolic events and breast
reported in observational studies have been appropriately confirmed
by the prospectively randomized studies. Only the cardiovascular
disease risks have
not been confirmed, instead they have been completely negated. Why?
Although there is no clear answer, it may be explained by the significant
improvement in cardiovascular health care that women have experienced
during the past 2 decades, which might have obscured the potential
cardiovascular benefits of EPT. Indeed,
20 and 30 years ago, cardiovascular disease was thought to be primarily
of men. Very few women were evaluated or treated for hypertension
and/or hyperlipidemia, two major cardiovascular disease risk factors.
women, ET/EPT might have been therapeutic, indirectly by improving
lipid profile and directly by decreasing plaque formation and
by inducing vasodilatation
through the regulation of nitric oxide, prostaglandin synthetase
and membrane ionic permeability.
During the past 15 years, women’s
heath care has changed dramatically, so that women with hypertension
especially those who participate in clinical trials, are
commonly being treated with potent lipid lowering agents and antihypertensive
medications. The cardiovascular protective effects of these medicines
would obscure any potential vascular benefits of ET/EPT. Consequently
only the adverse vascular
effects of ET/EPT
would be noted, since it’s potential beneficial effects have already
been usurped by the stronger cardiotropic statins and antihypertensive
In addition, had the patients at risk for fracture been
biphosphonates, I doubt very much that the protective effects of
ET/EPT on fractures would have been noted. This hypothesis is supported
recent publication of the Estrogen in the Prevention of Atherosclerosis
Trial (EPAT). In this prospective study, 222 postmenopausal women
with LDL cholesterol levels in excess of 130 were randomized to
17-beta estradiol or placebo and were angiographically monitored
for progression of coronary atherosclerosis. The results revealed
that the women randomized
to 17-beta estradiol experienced significantly less progression
of atherosclerosis than placebo group. However, in those study
patients who were also taking
lipid-lowering therapy (statins), 17-beta estradiol therapy did
not confer additional benefit on coronary atherosclerosis. It appears
then that for
cardiovascular protection, ET/EPT served its purpose in women’s health
when there was a need for it, prior to the widespread use of cardioprotective
Currently, with the vastly improved women’s health care, the
role of ET/EPT in cardiovascular protection is neither needed nor
safe. Indeed it is risky. The primary reasons for prescribing EPT
remain the same,
but the secondary gains are no longer there, because for most women
the risks are greater. The WHI data are very useful in allowing
us to quantify these risks.
The fact that the estrogen-only arm of the WHI study continues unabated,
supports the hypothesis that the progestin in the EPT preparation
may be mostly responsible for the increased risk of breast cancer
as well as atherosclerosis,
coronary heart disease, and stroke. Moreover, some may
argue that MPA may be particularly important for the cardiovascular
risks and that
a different progestin, such as micronized progesterone or norethindrone
acetate, may not confer similar risks. Indeed the PEPI study
found that the addition of MPA to CEE in postmenopausal women negated
some of the beneficial
effects of CEE on the lipid profile, whereas the addition of micronized
progesterone did not.
Moreover, animal studies have found that
MPA but neither NETA nor micronized progesterone negated
the beneficial effects
of estrogen on coronary plaque formation in animal studies. It
appears that different progestins may have variable effects
on atherosclerosis, and that among the various clinically available
may be particularly
deleterious to cardiovascular health. However, the results of
these animal studies may not apply to humans but may serve as hypothesis
that need to
be tested in prospectively randomized human clinical trials.
the WHI EPT findings can be generalized to other hormone preparations
For the present, the burden of proof for greater safety and efficacy
lies with the sponsors of the other products.
Recommendations for clinical practice
In response to the WHI data, the American College of Obstetricians
and Gynecologists (ACOG) issued guidelines regarding the administration
of ET/EPT and the management of menopausal women symptomatic
and or at risk for osteoporosis, breast cancer and cardiovascular disease.
these guidelines are appropriate and very useful given the
current knowledge of ET/EPT in women’s health. The ACOG recommendations
and my comments are listed below.
Individualize treatment. Women
will tolerate and respond differently to different preparations
and doses. I tend to use natural estrogens and progesterone as
much as possible
because I can easily measure serum levels which help me assess
and compliance. I especially prefer the transdermal preparation,
because it is more physiologic, yields constant serum levels
throughout the 24-hour day and avoids first pass through
the liver, which
is associated with non physiologic alteration of hepatic enzymes
and proteins, especially binding globulins for steroids, thyroid
and sex hormones as well as coagulation factors.
I use the lowest dose that will achieve benefits and avoid side
effects. This is a very important recommendation. It is true
of all therapies that we use, but it is especially important
for ET/EPT, which can result in life threatening side effects.
prospective, observational study conducted in healthy postmenopausal
women for the primary prevention of cardiovascular disease, it
was reported that the relative risk of stroke increased progressively
incremental increase in the dose of unopposed
relative risks (confidence intervals) of stroke with CEE at the
daily dose of 0.3 mg, 0.625 mg, and 1.25 mg were 0.54 (0.28-1.06),
1.35 (1.08-1.68), and 1.63 (1.18-2.26) respectively. Consequently,
one should start with the lowest dose (0.3 mg for
CCE, 0.5 mg for oral estradiol , 0.035mg for transdermal estradiol).
This dose may be progressively increased according to the patient’s
response but seldom should exceed double the starting dose. Similar
guidelines should be followed for progestins.
Use ET for women without a uterus and EPT with a uterus.
The importance of using EPT in women with a uterus is well known
to all gynecologists.
However, the optimal preparation and administration of HRT remains
elusive. It is clear by now that not all progestins have the same
on the body, especially on cardiovascular health. The type, sequence,
dose and duration of progestin administration should be carefully
Originally, when it became evident that unopposed
cancer in women with a uterus, progestins (usually in the form
of MPA) was administered for 7, 10, or 12 days each month, mimicking
the cyclic production
of progesterone by the premenopausal ovary. Although effective
in protecting against endometrial cancer, the cyclic administration
of EPT induced undesirable
uterine bleeding which caused many women to stop EPT. To avoid
cyclic bleeding and to improve compliance, the continuous and
combined EPT preparations
were introduced with prolonged exposure to progestin.
Since it appears from the WHI study that progestins may be primarily
risks of CVD, stroke and breast cancer, it may be prudent to
the duration of progestin treatment in postmenopausal women.
Several studies have demonstrated that the
cyclic administration of progestin (two weeks every 2-3 months)
may be as protective against endometrial cancer as the monthly
Moreover, if the minimally effective dose of both daily estrogen
and cyclic progestin (every 2-3 months) are used, most women will
not experience significant bleeding.
Long-term use of continuous combined, fixed dose HRT in asymptomatic
women should be stopped. Asymptomatic women do not need (nor will
they benefit) from ET/EPT and there is
no need for them to
use it. The potential benefit of EPT on bone loss and fractures
can be duplicated with other medications specifically designed
for this purpose. The biphosphonates (alondranate
and risedronate) are safe, effective, convenient (once per week
dose) and not associated
with life threatening side effects. Raloxifene (a selective estrogen
modulator) is also a good alternative for the prevention and treatment
of osteoporosis in patients not at risk for thromboembolic events.
raloxifene is not associated with an increased risk of either breast
cancer or cardiovascular events. In fact, data from the MORE study
besides protecting against bone loss and vertebral fractures, raloxifene
may be protective against the risk of breast cancer by as much
as 75%. Raloxifene was found not to increase risk or events
of cardiovascular disease.
Reassess the benefit-risk ratio with
each patient annually. Annual visits should include a review of
the reasons for taking ET/EPT and the current knowledge regarding
benefit ratio of this therapy.
It is quite possible that when all the data from the WHI studies
are available and reassessed, the benefit-risk ratio may change
and consequently our recommendations may be different. Currently
I assess the benefit-risk ratio by explaining the data as it
is now, and I remind the patient that the most important (if
not the only) reason for taking ET/EPT is the control of menopausal
symptoms. To find out whether the menopausal symptoms have resolved
or have become more tolerable, I invite the patient to discontinue
the therapy for a period of 4-8 weeks. If the symptoms recur
and are intolerable, or if in the patient’s mind the benefit
risk ratio is positive, we resume therapy. If it is negative,
we stop and consider alternatives. Our role should be to
the patient arrive at her own conclusion regarding her individual
benefit-risk ratio, based on the
scientific data we provide and the symptoms
that she experiences.
Until the recent publication of the WHI study, women initiated
and continued ET/EPT for a number of reasons, including vasomotor
symptoms and related quality of life issues (sleeping, mood,
vaginal dryness), osteoporosis prevention and treatment, and
With the new knowledge from the WHI study, we now know that EPT
confers no cardiovascular disease protection but, instead, carries
Although ET/EPT has been shown to be protective against osteoporosis
and related fractures, the associated risk of cardiovascular
and thromboembolic events and breast cancer preclude its use
for prevention of osteoporosis in
safer alternatives, such as raloxifene and biphosphonates. Raloxifene
may be especially attractive to older postmenopausal women not
at risk for thromboembolism or vasomotor symptoms, because of its
effects on breast cancer risk and potential benefits on cardiovascular
Currently, the only indications for EPT in menopausal
women are vasomotor symptoms and associated quality of life issues.
for these reasons, women should be advised to take the lowest
effective dose of these medications for as
short a time as possible.
I favor estradiol either orally or transdermally, starting
with daily doses of 0.5 or .05 mg respectively. If symptoms are
not adequately controlled
and serum estradiol levels are less than 50 pcg/ml, I increase
the daily doses to .75mg and .075 mg, up to a maximum
of 1 mg and .100
mg respectively. For the progestin preparation, I recommend micronized
progesterone orally, 200 mg at bedtime for 2 weeks every 1-3
months. If patients cannot tolerate micronized progesterone, I
recommend norethindrone acetate in combination
with estradiol either orally (Activella) or transdermally (Combipatch).
The duration of therapy must be individualized and reassessed yearly,
according to the current knowledge of the risks and benefits
and the patients’ symptoms.
This may require periodic interruption of the therapy to assess
the patient's symptoms. Our responsibility
is to provide patients with current scientific knowledge of
the risks and benefits of
EPT. Each postmenopausal woman should use
this knowledge (in combination with her menopausal symptoms and
response to HRT) to determine whether or not to continue or initiate
therapy. This approach, which requires ongoing dialogue between
physician and patient, empowers each postmenopausal woman to
actively participate with and take responsibility for
her own health care.
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