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by Lila E. Nachtigall, M.D.
Isoflavones - In the Management of Menopause
 Menopause is characterized
by a rapid and progressive
reduction in estradiol, the
endogenous form of the
steroid hormone estrogen.
This brings about many changes in a
woman’s body, some of which, like hot
flashes, are discomforting but not life-threatening.
Others, like loss of bone density
and decline in cardiovascular function,
have serious life-threatening consequences.
Many of these changes can be eliminated or
reduced with hormone replacement therapy
(HRT). Despite its benefits, however, some
women are not candidates for this treatment
and many others choose not to take it. As a
result there is growing interest among
women about natural alternatives to conventional
HRT. There are a number of herbal
and nutritional alternatives proposed for
management of symptoms and reduction of
health risks among menopausal women and
the group of phytoestrogens called
isoflavones are promising compounds. Red
clover is a valuable source of the four important
isoflavones (genistein, daidzein,
biochanin and formononetin) and clinical
data are now accumulating to indicate that
standardized extracts may provide a range of
health benefits in women.
Health risks associated with menopause
The median age of onset of menopause,
defined as the last menstrual period, is 51
years and is associated with a permanent loss
of ovarian follicular activity. However, most
women begin to experience signs of estrogen
deficiency as early as three to four years prior
to the last menstrual period, often manifested
as hot flashes, mood swings, night sweats,
insomnia, vaginal dryness and a variety of
other discomforting but not life-threatening
symptoms.
The postmenopause years present more
serious and potentially life-threatening
health risks to women, including significant
loss of bone mass during the first five to
seven years. This loss makes women particularly
susceptible to osteoporosis. In the USA
osteoporosis is responsible for 1.5 million
fractures annually, costing the nation $13.8
billion. According to the National
Osteoporosis Foundation, eight million U.S.
women already have osteoporosis and 15 million
more are at risk due to low bone mass.
In 1996, 505,930 women in the USA died
of cardiovascular disease and, according to
the American Heart Association, one in
two women will eventually die of heart
disease. After menopause, a woman’s risk of
cardiovascular disease and death from this
condition increases.
Advantages and disadvantages
of hormone replacement therapy
Estrogen replacement has been shown to
relieve vasomotor symptoms and vaginal
atrophic changes and reduce the risk of
osteoporosis, coronary artery disease, colon
cancer and probably Alzheimer’s disease.
Despite the apparent benefits of HRT,
however, researchers estimate that only
10–35 percent of postmenopausal women
use it. In addition, half of those who commence
HRT discontinue therapy within a year, often because of side effects such as
bleeding and breast pain or because of concerns
about a potential increase in risks of
breast and uterine cancer of thromboembolic
disease.
In fact, estrogen is contraindicated in
about 10 percent of postmenopausal
women, including those who have a past history
of estrogen-dependent malignancy or
clotting disorder associated with estrogen
use or active liver or thromboembolic disease.
Alternative options for managing menopause
HRT is not the only option for postmenopausal
women, however. Women who
cannot or do not want to take hormones
may decide to turn to natural remedies for
managing their menopausal symptoms and
risk factors. Indeed, non-pharmacologic
therapies, including herbal treatment, are
widely used but many remain relatively
unstudied by the scientific community. A
1998 report indicates that 42 percent of
adults have tried alternative medicines. And
according to a 1993 survey of 1,539 adults,
one in three respondents said they used at least
one alternative therapy in the past year. The
1998 survey estimated that out-of-pocket
expenditures for alternative therapies totaled
$27 billion a year. The amount is comparable
to that spent for all U.S. physician services.
Isoflavones and menopause management
Observational data provide evidence that an
isoflavone-rich diet may not only reduce the
prevalence of acute menopausal symptoms
but may also lower the risk of hormonerelated
cancers. Of the broad range of estrogenic
substances in plants (phytoestrogens)
the isoflavones have the most potent estrogenic
activity. Although not as potent as
17ß-estradiol, in populations with high
legume intake isoflavones may be present in the body at levels up to 1,000 times those of
steroidal estrogens. They compete with
endogenous estrogen for receptor sites and if
endogenous levels are high, isoflavones may
exhibit anti-estrogenic properties. If endogenous
levels are low, as in menopausal women,
isoflavones may exhibit estrogenic properties.
Like the synthetic estrogen antagonists
tamoxifen and raloxifene, isoflavones appear
to possess tissue selectivity in their agonist and
antagonist effects. This effect is explained by
the existence of two types of estrogen receptors—alpha and beta. Alpha receptors are the
main receptors in the breast and uterus and
beta receptors are mainly found in bone and
the cardiovascular system. Estradiol has affinity
for both receptors whereas the isoflavones
are more selective for beta receptors.
Isoflavones are found mainly in plants of the
legume family and four isoflavones have been
described. Whereas the soya plant contains
only genistein and daidzein, other legumes
like chickpeas, lentils and alfalfa sprouts contain
biochanin and formononetin, but the red
clover plant contains all four.
The majority of plant isoflavones exist in
the form of glycosides; that is, they are
attached to a sugar molecule. To become biologically
available these glycosides must be
cleaved in the gut to yield a sugar-free aglycone.
After conversion to the aglycone, about
one-third is absorbed as free isoflavones and
the remaining two-thirds are fermented by
bacteria in the large bowel into metabolites
such as equol, which are then absorbed.
Asian diets and isoflavones
Interest in isoflavones followed observations
that Asian women, who consume more
isoflavones than Western women, experience
fewer menopausal symptoms.
A study of menopausal Thai women, for
instance, demonstrated that only 27 percent
experience hot flashes and 24 percent report
nights sweats. In contrast, up to 85 percent of
Western women experience vasomotor symptoms.
A study of Japanese women also found
lower incidence of vasomotor instability
among them compared with Western women.
While these epidemiologic studies do not
establish a cause and effect relationship, the
lower incidence of climacteric symptoms may
be attributable to diet rather than genetic disposition
—a theory supported by a review article
showing that Asian people who consume
more Western diets have a higher risk of
chronic and degenerative disease, including
hormone-dependent cancers, colon cancer and cardiovascular disease, compared with
those who consume traditional Japanese diets.
Researchers began to suspect that
isoflavones were the beneficial substance
because they are found in abundance in East
Asian diets. One study found that the excretion
of isoflavonoids in urine was much higher
in Japanese women than in American and
Finnish women. Food sources of isoflavones
include legumes, especially soy and soy products
like tofu, sweet potatoes, carrots, garlic, red
wine, barley, green beans, oats and pumpkin.
Effect of isoflavones on acute symptoms of menopause
A number of studies have been conducted on
the effect of isoflavones on hot flashes, the
commonest menopausal symptom. Some suggest
these phytoestrogens impart benefits and
others do not. The final results of one randomized,
double-blind trial of a red clover
isoflavone extract, for example, concluded
that “there was no significant difference
between active and placebo groups in the
reduction in hot flashes . . .” during a three month
period.
This result may have been confounded due
to protocol violations by women in the placebo
group who introduced isoflavones into
their diet as evidenced by their presence in the
urine collected at the final study visit.
However, analysis of pooled data from all subjects
regardless of treatment group at week 12
revealed a statistically significant correlation
between the reduction in hot flashes and urinary
isoflavones excretion, with all subjects
with urinary isoflavones excretion greater than
2 mg per day reporting a reduction in hot
flashes greater than the placebo response. This
indicated that as isoflavone intake increased
there was a greater reduction in hot flashes.
A second randomized, double-blind trial
of the same proprietary red clover-derived
isoflavone preparation (Promensil; Novogen
Ltd, Australia), given at a dose of 40 mg per
day, produced a 75 percent reduction in hot
flashes after 16 weeks in 30 women. The difference
between placebo and isoflavones
groups was significant (p<0.001). A similar
open trial using the same red clover extract
reported significant improvements in hot
flashes and night sweats.
Effect of isoflavones on osteoporosis
Studies of the effects of isoflavones on bone
health have produced mixed results.
According to two multicenter studies, the synthetic
isoflavone ipriflavone prevents bone loss in postmenopausal women with low bone
mass. Four hundred and fifty-three women
were given either 200 mg of oral ipriflavone
three times a day or placebo for two years. All
of the women were also given 1 g of calcium
daily. In both studies, the ipriflavone group
maintained bone mass, whereas the placebo
group experienced a decrease in bone mineral
density. Overall there was a bone-sparing
effect of 1.6 percent in one study and 3.5 percent
in the other with ipriflavone. The synthetic
isoflavone prevented both axial and
peripheral bone loss and was well tolerated.
However, in a more recent study no effect of
ipriflavone on bone density was observed and
adverse hematological effects were reported.
Recently data has been presented on a
year-long, double-blind placebo-controlled
study involving 107 women showing that 40
mg of red clover isoflavones decreased the rate
of loss of bone mineral density (BMD) and
bone mineral content (BMC) in lumbar spine
of pre- and peri-menopausal women. No differences
were seen between treatment groups
in hip BMD, BMC or urinary bone markers.
Similarly, a study using Rimostil, which
contains the proprietary isoflavone blend
Clovone (Novogen Ltd, Australia), found that
this supplement increased BMD in the proximal
radius and proximal ulna, implying that
these isoflavones have significant estrogenic
activity in bone. The compound did not cause
uterine bleeding or any significant changes in
endometrial thickness.
Other research has shown that bone
density increases in women consuming soyenriched
bread, compared with a control
group eating wheat bread.
Isoflavones and cancer
A review of the clinical, epidemiological
and mechanistic evidence indicates that
isoflavones may possibly have anti-carcinogenic
effects. Tham and colleagues cite studies, for
instance, that suggest phytoestrogens may
reduce breast and endometrial cancer risk.
Another study found a reduced risk of
breast cancer in women with elevated urinary
isoflavones. The investigators noted that some
researchers have postulated that isoflavones
may act as anti-estrogens by competing with
estradiol for binding sites, thereby inhibiting
the growth of hormone-dependent cells. They
may also stimulate SHBG in the liver, thus
reducing the amount of “free” estradiol in the
plasma.
In a review of five other studies on soy
and breast cancer risk, three suggested an association between reduced risk for premenopausal
breast cancer and soy. The
fourth study was the only one that showed a
decreased risk of postmenopausal breast
cancer, whereas the final study found a nonsignificant
decrease in breast cancer risk
associated with tofu intake. In contrast,
another study reported the cytologic
detection of epithelial hyperplasia in
29 percent of women receiving soy supplements
for six months. This suggests that
prolonged intake of soy protein isolate has a
stimulatory effect on the premenopausal
female breast, characterized by increased
secretion of breast fluid, the appearance of
hyperplastic epithelial cells and elevated
plasma estradiol. However these data were
from a pilot study which did not include a
control group and the conclusions need to
be confirmed by further research.
The potential mechanisms for these epidemiological
observations are multiple.
Isoflavones have been described as having
anti-cancer activity against various types of
human and animal cancers. Known biological
effects of these compounds which may
contribute to their anti-cancer action are
(a) modulations of signal transduction mechanisms through inhibition of enzymes such as protein tyrosine kinases and DNA topoisomerases I and II,
(b) interruption to cell cycle kinetics by blocking cells in the G2/M phase of mitosis,
(c) induction of terminal differentiation of cancer cells,
(d) inhibition of enzymes involved in the synthesis of androgens (inhibition of 17 beta-hydroxysteroid
dehydrogenase and 5 alpha-reductase) and estrogens (inhibition of aromatase),
(e) possession of natural antioxidant activity,
(f ) induction of apoptosis in cancer cells,
(g) inhibition of angiogenesis,
(h) estrogen receptor antagonism and
(i) promotion of cancer cell adhesion.
Potential clinical use of isoflavones in menopause management
Safe and effective alternatives to HRT would
be a welcome addition for the treatment of
menopausal symptoms and to improve cardiovascular
health and slow the rate of bone
loss. There is now a substantial body of evidence
to suggest that isoflavones offer benefits
but more interventional trials are
required to reach definitive conclusions.
Isoflavones derived from red clover have
been shown in controlled studies to have a
positive impact on bone density, cholesterol
profiles and on arterial compliance.
Epidemiologic studies suggest that an intake
of more than 40 mg a day of isoflavones has
some protective effect against cancers. Also
positive is the low side-effect profile with a
lack of stimulating effect on endometrial
and breast tissue in studies to date. The
evidence pointing to a therapeutic effect on
menopausal symptoms like hot flashes is
mounting but further proof is needed with
larger controlled studies.
For women who do not want to take
estrogen, isoflavone-containing foods may
provide some benefits but it is unlikely
that foods can offer an adequate alternative
for women seeking estrogen’s full and welldocumented
benefits: protection against
heart disease and osteoporosis. If despite
estrogen’s proven advantages, a patient
decides to choose the isoflavone approach
over HRT, she needs to realize that it would
be difficult to obtain the needed dosage
from diet alone. Certainly caloric intake
would have to increase significantly to do so.
Standardized supplements would probably be
required.
Editor’s Note: Research indicates men also benefit from dietary estrogens and the
incidence of both benign prostatic hyperplasia (BPH) and prostate cancer are markedly reduced in countries where high legume intake is practiced, due in part to the hormone balancing effect of plant
estrogens (anti-androgen action) and the inherent ability of isoflavones to act as inhibitors of 5 alpha-reductase, the enzyme which converts testosterone into the more potent dihydrotestosterone. It
is also possible that the cardiovascular benefits which women experience after estrogen supplementation can be achieved in men.
For references send a SASE to totalhealth magazine.
Lila E. Nachtigall, M.D. is a professor of obstetrics and gynecology at the New York University School of Medicine. Dr. Nachtigall is the president of the North American Menopause Society.
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