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Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 1

Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 1

ABSTRACT: There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 47 breast cancer experts and 13 patient advocates participated. The proceedings of the conference will be published in six installments in successive issues of oncology. This first part defines the problem and explores its magnitude and ramifications for patient management. [ONCOLOGY 1(13):109-136, 1999]


Introduction

Henry Burger, MD: Estradiol levels are well preserved until
the onset of the menopausal transition—a phase in a woman’s
life marked by physiologic changes that indicate the approach of
menopause. During that transition, hormone levels may fluctuate
widely and symptoms begin to occur. Concentrations of estradiol fall
by about 90% during the time when the final menses are experienced,
although the lowest levels are not usually reached until 1 to 3 years later.

Interestingly, despite that very marked fall in estradiol, the impact
of menopause may vary from woman to woman in the same community and
among women in different communities and different countries.
Community surveys indicate that the impact of menopause is not very
great for the majority of women but is very great for a minority.

Clinical Indications for HRT

Hormone replacement therapy (HRT) may be used for both short-term
symptom control and for the long-term prevention of a number of
disorders resulting directly or indirectly from menopause (Table
1
). Short-term symptom control may be required for hot flashes;
symptoms that result from lower genital tract atrophy, such as
difficulty with intercourse or urination; sleep disturbances; or mood disturbances.

For long-term disease prevention, a number of indications for
systemic hormone therapy are generally accepted. Apart from the
preservation of postmenopausal quality of life, however, none of
these indications has been rigorously established. The consensus view
is that established indications include a reduction in the risk of
osteoporotic fracture, treatment of established osteoporosis, and a
reduction in atherosclerotic cardiovascular disease risk,
particularly myocardial infarction.

Reducing Osteoporotic Fracture and Treating Osteoporosis

Osteoporosis is a major cause of morbidity, mortality, and health
expenditure but with variable prevalence worldwide. About 75 million
women in the United States, Europe, and Japan are affected. One in
three postmenopausal women will suffer from the consequences of this
disease, the majority being elderly. In US women, about 1.3 million
osteoporotic fractures occur annually, at a cost of $10 billion to
the health-care system. Most significant is hip fracture, which may
result in a 1-year mortality of 12% to 20% and frequently leads to a
loss of the woman’s independence.

Estrogen deficiency increases bone remodeling and leads to bone loss.
Estrogen administration reverses that process, although all of the
mechanisms involved are still unclear. The effect ceases when therapy
is discontinued.

Many believe that the greatest benefit of estrogen is seen when
treatment is initiated within 5 years of menopause, although there is
no consensus on when treatment should be initiated or for how long it
should be continued. No controlled clinical trials have shown a
reduction in hip fracture in women given estrogen replacement
therapy. In placebo-controlled studies, only a small number of
patients have shown actual reductions in fractures, such as vertebral fractures.

The dose of estrogen is important, while the route is probably not.
The effects of progestins on bone mineral density are variable.

Reducing Cardiovascular Disease

The impact of HRT on cardiovascular disease is generally regarded as
a major focus of research. Mortality data from Australia in 1993
showed that 47.5% of all deaths in women were due to cardiovascular
disease and 23.8% were due to coronary heart disease.[1] In contrast,
breast cancer accounted for 4.7% of deaths, which is approximately
one-fifth of total coronary heart disease mortality.

Mortality from breast cancer, when compared to mortality from heart
disease, varies as a function of the age group in which that
comparison is made. Rather old US data on age-specific death rates
indicate that breast cancer mortality never reaches the figure for
heart disease. However, more recent data suggest that the prevalence
rates may converge, particularly in the 50- to 60-year-old age bracket.

To demonstrate an effect of estrogen in the prevention of coronary
heart disease, randomized, controlled clinical trials are required.
Observational and case-controlled studies show that estrogen probably
reduces the risk of heart disease, and the general consensus favors
that conclusion. Rigorous proof will be lacking, however, until the
proper studies are reported.

Primary Prevention—With respect to primary prevention, a
variety of observational epidemiologic studies have shown that
estrogen users have a reduced risk of developing heart disease;
generally, the magnitude of this reduction is approximately 50%.
Estrogen administration has demonstrated acute and chronic effects in
both human and animal studies that are consistent with such a
protective effect. The mechanisms of estrogen’s effects are
large in number and include favorable effects on serum lipids, as
well as a wide variety of direct effects on the vasculature. Despite
figures to the contrary, the more recently published major studies
suggest that progestins do not exert a major influence on the
beneficial effects of estrogen.

Secondary Prevention—With respect to secondary
prevention, a number of observational studies show that estrogen
therapy produces an even greater risk reduction of up to 80% in
subsequent disease or death among women who have already had a heart
attack or who have clear clinical evidence of coronary artery
disease. A number of prospective studies focusing on secondary
prevention are underway. One of these trials, the Heart and
Estrogen-Progestin Replacement (HERS) trial, was recently
reported.[2] [Editors’ Note: Although the HERS trial was
reported after the 1997 conference, its results were considered
important enough to be added to the published proceedings.]

This study examined the effect of conjugated estrogens (Premarin)
plus continuous medroxyprogesterone acetate in the secondary
prevention of heart disease. Of interest was the observation of an
increase in new cardiac events during the first year of the study
when estrogen-medroxyprogesterone was compared with placebo. During
the third to fifth years of observation, a reduction in new coronary
events occurred. These results suggested an initial prothrombotic
effect of estrogen and a longer-term beneficial effect. However, no
overall effect of estrogen was documented. Longer-term studies that
rigorously control for all possible variables are now needed and
should be forthcoming.

Other Possible Indications

Several other conditions can be considered as possible indications
for hormone replacement therapy. One that has arisen recently is the
possibility of reducing the risks of and even treating
Alzheimer’s disease. A number of studies also suggest that HRT
may reduce the risk of colon cancer and some forms of arthritis.
Although there are very little data, estrogens also may be beneficial
in treating a number of complications related to macrovascular
disease in diabetics.

Alzheimer’s disease is an idiopathic degenerative disease
of the brain, the risk of which increases progressively beginning at
40 years of age. Its prevalence may be as high as 5% in people over
the age of 65 and is much higher in those over age 85.
Alzheimer’s disease is probably more frequent in women, although
this has not been established with certainty, and men may have more
vascular dementia then women.

A number of symptoms characterize Alzheimer's disease. These
initially include memory loss and a number of other clear-cut
neurologic disorders; personality and emotional changes occur later.
Progression of Alzheimer’s disease leads to incontinence, gait
disturbance, mutism, and dependency, typically over a 6- to 12-year period.

There are several theories relating estrogens to Alzheimer’s
disease. Evidence exists that women with a history of myocardial
infarction and menopausal women, who, by implication, have lower
estrogen levels or lower estrogen exposure, have an increased
likelihood of developing Alzheimer’s disease. Most women with
Alzheimer’s disease are thinner and, as a result, would have
lower estrogen levels. They are also more likely to sustain hip
fractures, which suggests an association with estrogen deficiency.

Oophorectomy may lead to rather specific deficits in some aspects of
cognitive function, such as verbal recall, which are corrected by
giving estrogen. Experimental evidence shows that estrogen has direct
trophic effects on the basal forebrain cholinergic neurons. The
degeneration and loss of the synapses of these neurons are believed
to be major factors in the pathogenesis of Alzheimer’s dementia.
Estrogen, which may maintain the levels of nerve growth factor and
brain-derived growth factor, may thus be relevant to the disease.

Several observational epidemiologic studies have shown a 25% to 50%
reduction in the relative risk of Alzheimer’s disease with the
use of estrogens. A relationship to duration of use is apparent in
some studies but not in others. A number of very small treatment
studies suggest that estradiol itself and estrone sulfate may improve
both cognitive and affective function in women with probable or
relatively early-stage Alzheimer’s disease.

Thus, a decreased risk of Alzheimer’s disease may be a reason to
consider postmenopausal hormone therapy. There is considerable debate
over whether progesterone may reverse the beneficial effects of
estrogens on Alzheimer’s disease.

Perhaps one of the more striking studies on the effect of estrogen is
a paper by Tang and colleagues published in 1996.[3] This
community-based study of aging in New York City involved 1,282
nondemented elderly women who, at the beginning of the study, were 74
years old on average. Estrogen use was associated with a
statistically significant, 40% reduction in the risk of developing
Alzheimer’s disease: 6% of estrogen users vs 16% of nonusers
developed the disease. The age of onset of the disease was later in
estrogen users, and none of the 23 women who were taking estrogens at
the outset of the study actually developed Alzheimer’s disease.

In 1996, Kuller published a very useful critical review of the data
regarding estrogens.[4] He argued that, of the possible benefits of
estrogen use in Alzheimer’s disease, only its vascular effects
on the pathogenesis of the disease are solidly based. According to
Kuller, there is little evidence of a major gender difference in the
prevalence or incidence of Alzheimer’s disease. He contended
that the data on estrogen’s effects on cognitive function are
equivocal. There is also the paradox of individuals with higher
estrogen levels having greater longevity and, hence, a higher risk of
developing Alzheimer’s disease.

In Kuller’s view, clinical trials, although very expensive, are
essential and probably worth the cost. His overall conclusion is that
the possibility that estrogen therapy may prevent Alzheimer’s
disease is a hope without solid basis at this point in time.

Long-Term Risks of HRT

The long-term risks of hormone therapy have been widely discussed.
Unopposed estrogen substantially increases the risk of endometrial
cancer, and concomitant progestin use largely abrogates this effect.
There is some question as to whether the abolition is totally or only
partially complete.

With regard to breast cancer, ever- use or short-term use of estrogen
has not been associated with an increased risk. In a number of
studies, long-term use appears to be associated with an increased
risk on the order of 30%. Questions about surveillance bias and
patient selection bias (ie, the withholding of estrogens from
individuals at increased risk) remain as confounding factors. Also,
the effect of added progestins is unclear.

Since current data indicate that breast cancer is more common than
heart disease in women between 50 and 65 years old, perhaps we need
to be particularly careful about recommending HRT in that age group.
Most women, however, are likely to derive an overall benefit from
estrogen because of the reduction in heart disease, with only a small
increase in the risk of developing breast cancer.

“Established” contraindications to hormone therapy
include a history of breast and endometrial cancer, liver disease,
and venous thromboembolism. In some of the older publications,
established heart disease was also thought to be a contraindication,
and this has been reconfirmed by the HERS study results. Undiagnosed
vaginal bleeding, pregnancy, and certain pregnancy-associated
disorders are universally regarded as contraindications.

There remains great controversy over the use of hormone therapy in
women with a history of breast cancer. A 1997 review by
Vassilopoulou-Sellin et al suggested that hormone therapy does not
appear to have a pronounced adverse effect on cancer outcome,[5]
although the number of patients studied and the resulting amount of
data are small. It will be important to discuss in this conference
whether women with a history of breast cancer should be denied
hormone therapy when there are other conditions present for which HRT
is indicated.

With regard to liver disease, a recent review[6] suggested that
hormone therapy should be considered in all menopausal women with
chronic liver disease, regardless of whether menopause was
spontaneous or surgically induced, and regardless of the presence of
primary or secondary amenorrhea. Women with primary biliary cirrhosis
or sclerosing cholangitis from alcohol or tobacco use or those who
are receiving long-term steroids for autoimmune hepatitis are at
particular risk for osteoporosis and ought to be treated with estrogens.

With regard to venous thromboembolism, three observational studies
published in late 1996 found an association between hormone therapy
and venous thromboembolism, although that would only confer an extra
risk of about 1 case per 5,000 women per year. Five other studies
found no association. In a very good review published in 1997,
Douketis et al[7] argued that all of these studies have methodologic
problems that preclude one from making definitive conclusions about
the association, and that the biological plausibility of the
association is not convincing.

Summary

As summarized in Table 1, estrogens
are generally indicated for women with symptoms of estrogen
deficiency, such as hot flashes and urogenital atrophy, depending on
their severity. For women without significant risk factors for heart
disease, osteoporosis, and Alzheimer’s disease, the indications
for hormone therapy are equivocal. For those with significant risks
of heart disease or osteoporosis, the benefits strongly outweigh the risks.

Current contraindications to HRT should be viewed with skepticism, as
most may not be valid. Finally, ongoing clinical trials hopefully
will provide helpful guidelines for the use of hormone replacement.
Other options must always be considered for management, including
advice on lifestyle modifications, avoidance of smoking, dietary
measures, exercise, lipid-lowering agents, and bisphosphonates.

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