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- Margo Woods, Donna Speigelman, Ellen Hertzmark, Ann LaBrode,
and Christopher Longcope; Tufts University, Boston, MA, USA.
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- A 7-mo, double-blind, crossover study was designed to determine
whether a soy supplement containing 45 mg/d of phytoestrogen would
decrease the number and intensity of hot flashes and night sweats
in menopausal women (ages 45–58 y) reporting more than five
hot flashes daily. An alternative to hormone replacement therapy
(HRT) for the alleviation of hot flashes would be welcomed by
the medical community and by many patients who do not choose to
use HRT. Eighty-five women completed the protocol that started
with 2 wk of baseline data, recording menopausal symptoms, and
collecting blood for the determination of baseline hormones and
gonadotrophins. Women were randomly assigned to receive a soy
or placebo supplement for 12 wk. A daily record of symptoms was
kept and a blood sample was obtained at the end of the12 wk. One
month of washout was followed by the alternative treatment for
a second 12 wk and repeated data collection. Serum levels of phytoestrogens
were determined in a subsample of the women (n = 7) to determine
the serum levels achieved on the soy supplement to compare with
levels reported in Asian women. A control group of women (n =
45) was recruited that reported fewer than one hot flash daily
for a baseline period of 2 wk to obtain data on hot flashes, hormone
levels, and gonadotrophins in women in the same age category and
stage of menopause who were experiencing a low level of hot-flash
symptoms. A 22% and 26% reduction in the frequency of hot flashes
was reported during both the soy- and placebo-supplemented phases
of the study, respectively, compared with baseline, but no difference
was observed in the reported number or intensity of the hot flashes
when the soy and placebo phases were compared. Endogenous hormones,
however, were altered with a significant decrease in serum estradiol
in the soy phase compared with baseline (P = 0.003) and compared
with the placebo (P = 0.03). Decreases in sex hormone-binding
globulin (P = 0.0001) and increases in follicle-stimulating hormone
and luteinizing hormone (P = 0.03 for both) compared with baseline
were also seen. Levels of serum phytoestrogen achieved in the
women while on the soy supplement were comparable and probably
higher than levels seen in the Asian population. A significant
inverse association was observed between levels of estrone sulfate
and the number of hot flashes reported (P = 0.02).
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- Lon White; Pacific Health Research Institute, Honolulu, HI,
USA.
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- This investigation used the resources of the Honolulu Heart
Program, a longitudinal study of Japanese-American men established
in 1965 for research on heart disease and stroke. Questions regarding
frequency of consumption of tofu and 26 other foods were asked
at interviews in 1965–1967 and again in 1971–1974. Cognitive
testing was done (n = 3734) and cases of dementia identified (n
= 225) at the 1991–1993 examination, when participants were
aged 71–93 y. Atrophy was assessed by neuroimaging (n = 574)
or autopsy (n = 290). Cognitive test data were also analyzed for
wives of a sample of study participants (n = 502) who had been
living with the participants when their dietary interviews were
done. Poor cognitive test performance in late life was associated
with higher midlife tofu consumption. An independent association
of similar size and direction was apparent in wives of cohort
members, with the husband's answers used as proxy for the wife's
consumption. Midlife tofu consumption was independently associated
with low brain weight and with ventricular enlargement. Independent
associations of more frequent midlife tofu consumption with clinically
diagnosed Alzheimer's disease and with poor cognitive functioning
among nondemented subjects were demonstrated. Associations generally
followed a dose-response pattern, were statistically significant
after all relevant and potentially confounding factors were controlled
for, and remained apparent after stratifying by age or obesity.
These data suggest that regular consumption of tofu over many
years in middle life may have an adverse influence on brain aging
manifest as accelerated atrophy, cognitive decline, and a lowering
of the threshold for the clinical manifestations of Alzheimer's
disease. We speculate that these may reflect chronic suboptimal
neuronal plasticity caused by isoflavone inhibition of tyrosine
kinase activity, interference with estrogen-related mechanisms,
or both.
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- M. M. Rice1,2, A. B. Graves6, S. M. McCurry3,
L. Gibbons4, J. Bowen5, W. McCormick2,
and E. B. Larson2; Departments of 1Epidemiology,
2Medicine, 3Psychosocial and Community Health,
4Environmental Health, and 5Neurology, University
of Washington, Seattle, WA, USA; 6Department of Epidemiology
and Biostatistics, University of South Florida, Tampa, FL, USA.
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- Several epidemiologic and basic neurobiological studies suggest
that estrogen may have a beneficial influence on brain function.
We previously found a modest beneficial association between current
unopposed estrogen use (ERT) and cognitive change in female participants
of the Kame Project. The purpose of the present study was to determine
whether the consumption of tofu, an isoflavone-rich food, influenced
cognition in men and women. A secondary aim was to determine whether
tofu consumption modified the association between ERT and cognition
in women. Subjects were 767 women and 634 men participating in
the Kame Project. The Kame Project is a longitudinal cohort study
of Japanese Americans aged 65+ y living in King County, WA. The
100-point Cognitive Abilities Screening Instrument (CASI) was
measured at the baseline and 2-y follow-up examinations. Tofu
consumption was categorized as low (< 1/wk), moderate (1–2/wk),
and high (3+/week). All analyses were adjusted for age, education,
and language spoken at the interview. In addition, baseline CASI
score was adjusted for when the 2-y change in CASI score was examined
and surgical menopause was adjusted for when the tofu- ERT interaction
was examined.
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- Cross-sectional results: High tofu consumers had significantly
lower CASI scores than did low and moderate consumers in the cohort
as a whole (P for trend = 0.03). This trend was not significant
in men or in women who had never used ERT. Among women who were
current ERT users, a significant negative association was observed
between tofu consumption and CASI score (P for trend = 0.04).
CASI scores were higher in current ERT users than women who had
never used ERT for the low and moderate tofu consumers but not
the high tofu consumers.
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- Longitudinal results: Overall, most men and women showed slight
improvements in their CASI score over the 2-y period. No associations
were observed between tofu consumption and 2- y change in CASI
score, although men and women who were modest tofu consumers showed
the greatest improvements in their CASI scores. An important limitation
to this study was that total isoflavone exposure was not measured
in this cohort. Data from a sample of female Kame participants
suggested that tofu accounted for only about half of the soy-derived
isoflavones consumed by this population.
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- The cross-sectional data suggested that high tofu consumption
was associated with lower cognitive scores and opposed the beneficial
association between ERT and cognitive scores in women. On the
other hand, the longitudinal data suggested that tofu consumption
was not associated with the rate of cognitive change in older
Japanese American men and women and that tofu consumption did
not appear to oppose the beneficial association between ERT and
cognitive change in women.
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- Clinton D. Allred, Kimberly F. Allred, and William G. Helferich;
Division of Nutritional Science and Department of Food Science
and Human Nutrition, University of Illinois, Urbana, IL, USA.
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- The phytoestrogen genistein stimulates growth of estrogen-dependent
human breast cancer (MCF-7) cells in vivo. Genistin is the glycoside
form of genistein and the predominant form found in plants. It
is generally believed that genistin is metabolized to genistein
in the gut. However, it is unclear whether the rate of this metabolism
is sufficient to produce a level of genistein capable of stimulating
estrogen-dependent breast cancer cell growth. We hypothesized
that dietary genistin stimulates tumor growth similar to that
observed with genistein in athymic mice. To test this hypothesis,
genistin or genistein was fed to athymic mice containing xenografted
MCF-7 tumors. Mice were fed either genistein at 750 ppm or genistin
at 1200 ppm, which provides equimolar concentrations of genistein
in both diets. Tumor size was measured weekly. At completion of
the study, half the animals were killed and tumors were collected
for cell proliferation analysis. Incorporation of BrdU into cellular
DNA was used as an indicator of cell proliferation. Dietary genistin
resulted in increased tumor growth rate and cell proliferation
similar to that observed with genistein. The remaining mice were
switched to diets free of genistin and genistein. Removal of the
isoflavones from the diet resulted in tumor regression. In summary,
genistin, like genistein, can act as an estrogen agonist to increase
proliferation of estrogen-dependent breast cancer cells, and on
its removal tumors regress.
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- D. M. Sheehan1, K. B. Delclos1, D. R.
Doerge1, W. S. Branham1, and R. R. Newbold2;
1 National Center for Toxicological Research, Jefferson,
AR, USA; 2National Institute for Environmental Health
Sciences, Research Triangle Park, NC, USA.
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- A dose range finding study was conducted by feeding genistein
to Sprague-Dawley rats at 0, 5, 25, 100, 250, 625, and 1250 ppm
in a soy-free diet, from gestation day 7 to postnatal day 50.
Plasma levels ranged from about 10 nmol/L to 10 µmol/L. Adverse
effects included hypertrophy and hyperplasia of the mammary ducts
and acini in males at 25 ppm and in females at 625 ppm. Hypospermia
at the head of the epididymis, inflammation of the dorsal prostate,
and asynchronous cycles of the uterus and vagina were observed
at 625 ppm. Degeneration of the ovaries and seminiferous tubules
was seen at 1250 ppm. There was a dose-dependent decrease in thyroid
peroxidase activity at 25–1250 ppm. Thyroid peroxidase activity
is known to be inhibited in vitro by genistein, and the prevalence
of autoimmune thyroiditis was reported to be increased in children
fed soy infant formula.
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- In a separate study, genistein (1–100 µg) was injected
into neonatal mice daily on postnatal days 1–5 and the mice
were killed at 18 mo. Polyovular (multioocyte) follicles, uterine
epithelial hyperplasia, hypoplastic uteri, and uterine adenocarcinoma
were observed. These are similar to the lesions reported earlier
to be induced by diethylstilbestrol in mice by using the same
treatment protocol. In addition to genistein, 45 other phyto-
or mycoestrogens were assayed in a uterine estrogen receptor competitive
binding assay. Twenty-nine of these competed and had a wide range
of relative binding affinities. The number of naturally occurring
chemicals that can bind to the estrogen receptor suggests that
more intense or additional effects may be expected from exposures
to multiple estrogenic chemicals from plants.
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- These findings show a significant number of adverse effects
from genistein in estrogen target organs, including malignancies.
Some of these effects occur at low doses, consistent with findings
from other estrogens. Additionally, genistein inhibition of thyroid
peroxidase suggests the possibility that this mechanism may be
responsible for goiter and autoimmune thyroiditis. The results
of these studies have been used to design an ongoing multigeneration
study with genistein that will examine, among other endpoints,
reproductive fitness.
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- Retha R. Newbold, Wendy N. Jefferson, Elizabeth Padilla Banks,
and Bill C. Bullock; Developmental Endocrinology Section, Laboratory
of Toxicology, National Institute of Environmental Health Sciences,
Research Triangle Park, NC, USA.
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- Exposure to synthetic and naturally occurring estrogenic compounds
results in permanent alterations in the developing organism if
exposure occurs during the critical stages of differentiation.
Reports from our laboratory showed that perinatal exposure of
mice to diethylstilbestrol (DES) results in impaired fertility,
structural malformations, and lesions of the reproductive tract.
In fact, long-term consequences of exposure to DES at 2 µg/(pup·d)
on days 1–5 include a high incidence (95%) of uterine carcinoma
in animals older than18 mo. Doses less than 2 µg/(pup·d) also
result in long-term adverse effects. Thus, the developing reproductive
tract appears to be extremely sensitive to perturbation by compounds
with estrogenic activity. Because the nutritional and pharmaceutical
use of phytoestrogens increased over the past few years mainly
because of its reported beneficial effects, we investigated the
potential risks posed by genistein if exposure occurs early in
development. We tested the possibility that developmental exposure
to this compound would influence morphological, functional, and
biochemical markers known to be estrogen sensitive. Uterine epithelial
cell proliferation and induction of uterine lactoferrin and complement
C3 were increased in response to genistein. Although, lactoferrin
was previously reported to be constitutively produced in the uteri
of neonatally DES-treated mice as early as 2 mon prior to the
development of uterine carcinoma, the role of this protein in
the induction of neoplasia, either as a marker or contributing
factor, remains to be determined. However, lactoferrin and other
marker proteins are induced by developmental exposure to genistein.
The interaction of genistein with the estrogen receptors a and
ß was investigated. Further, mice were followed to evaluate a
potential increased risk for histological abnormalities, including
uterine tumors later in life. Many of the long-term effects observed
after DES treatment, including uterine adenocarcinoma, were observed
after developmental exposure to genistein. Similarities between
the effects of DES and genistein point to the need for further
mechanistic studies in phytoestrogens and the role in long-term
effects that follow developmental exposure.
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