вход по аккаунту


Estrogenisoflavone interactions in cynomolgus macaques (Macaca fascicularis).

код для вставкиСкачать
American Journal of Primatology 71:722–731 (2009)
Estrogen/Isoflavone Interactions in Cynomolgus Macaques
(Macaca fascicularis)
Wake Forest University Primate Center, Department of Pathology, Section on Comparative Medicine, Wake Forest University
School of Medicine, Winston-Salem, North Carolina
Soy isoflavones are phytoestrogenic components of dietary soy, which are widely consumed for their
potential health benefits. Soy isoflavones appear to decrease breast and endometrial cancer risk in
human observational studies, but paradoxically stimulate growth of breast cancer cells in culture and
uterine enlargement in rodents. We have shown that these compounds are not estrogenic in
cynomolgus monkeys even at relatively high doses, but that they reduce estrogen-induced proliferative
responses of the breast and endometrium. This effect may be mediated through estrogen receptor
interactions and/or modulation of endogenous estrogen metabolism. Interindividual variation in
isoflavone absorption and metabolism contributes to the degree of estrogen antagonistic effect. Our
recent studies have also shown that individual isoflavone metabolites such as glyceollins may have
unique selective estrogen receptor modulator-like activity, acting as tissue-specific antagonists without
agonist activity. Rodent studies and human epidemiologic data suggest that timing of exposure and dose
relative to endogenous estrogen concentrations are important determinants of effect, and studies of
dietary soy on breast development and pubertal maturation are under way. Because soy isoflavones are
both abundant in standard monkey chow diets and widely available as dietary supplements for human
beings, these findings have broad relevance to the health of human and nonhuman primates. Am. J.
Primatol. 71:722–731, 2009.
r 2009 Wiley-Liss, Inc.
Key words: genistein; breast; endometrium; diet
Soy isoflavones are phytoestrogenic components
of dietary soy, which are widely consumed for their
potential health benefits. Soy isoflavones in phytoestrogen pharmaceutical and ‘‘nutriceutical’’ products
are widely and increasingly marketed to the public
[Soyatech, 2008; Soy Foods Association, 2008].
Traditional soy foods are generally recognized as
safe, and the cardiovascular benefits of soy consumption have been sufficiently substantiated to warrant
approval as a health claim by the Food and Drug
Administration [1999]. However, the safety and
efficacy of many soy and soy isoflavone supplements
have not been fully evaluated, and so both the
potential risks and potential benefits remain unclear.
Soy isoflavones share structural similarities with the
mammalian hormone 17-b estradiol (Fig. 1) and in
fact are weak estrogens. They are relatively abundant in the circulation of people and animals who
consume soy. Given that estrogens are active in the
picomolar range of concentration and isoflavones
may be present at near micromolar concentrations
in blood and tissues of soy consumers, the potential
for biologic effect is real. Our studies have focused
on the potential for soy isoflavones to serve as
r 2009 Wiley-Liss, Inc.
endocrine modulators of estrogen action and
estrogen metabolism in the breast and reproductive
system. In general, we have found little direct effect
of isoflavones but clear antagonism of cancer risk
markers associated with estrogen exposure. Other
investigators have clearly shown that isoflavones can
produce estrogen-like promotion of breast cancer cell
growth in vitro and in rodent models [Wang et al.,
1996; Hsieh et al., 1998]. Regardless of whether their
aggregate effect is beneficial or otherwise, the widespread consumption of isoflavones in the human diet
and as supplements makes it imperative that we
understand their effects in greater detail. Herein we
review the evidence for direct and estrogen-modulatContract grant sponsor: NIH; Contract grant number: R01
Correspondence to: J. Mark Cline, Wake Forest University
Primate Center, Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine,
Winston-Salem, NC 27157-1040. E-mail:
Received 21 October 2008; revised 8 February 2009; revision
accepted 11 February 2009
DOI 10.1002/ajp.20680
Published online 25 March 2009 in Wiley InterScience (www.
Estrogen/Isoflavone Interactions in Macaques / 723
Fig. 1. Structure of the mammalian sex hormone 17-b estradiol compared with the soy isoflavone genistein.
ing effects of soy isoflavones on the reproductive
system in human beings and rodents in the light of
our recent findings in nonhuman primates.
Soy isoflavones appear to decrease breast and
endometrial cancer risk in human observational
studies. Dietary soy consumption early in life lowers
breast cancer risk in women. Cross-cultural studies
show three-fold lower age-adjusted rates of breast
cancer among Asian women who eat significant
amounts of soy compared with women in the United
States who eat little soy [Parkin et al., 1992].
Migrant studies [Dunn, 1977; Shimizu et al., 1991;
Stanford et al., 1995; Ziegler et al., 1993] have shown
that women of Asian origin have higher breast
cancer rates when they migrate to the United States
and adopt western diets and lifestyle compared with
the rates in regions of Asia with high soy consumption. This increase in breast cancer rates is more
pronounced in second and third generations residing
in the United States, suggesting that a transgenerational or an early-life effect may be present.
Migration studies are limited by a number of
confounders. The question of dietary soy effects can
be focused more closely by examination of case–control and cohort studies within a geographic
region. These more controlled but still observational
epidemiologic studies [Dai et al., 2002; den
Tonkelaar et al., 2001; Greenstein et al., 1996;
Hirayama, 1990; Hirose et al., 1995; Horn-Ross
et al., 2001, 2002; Ingram et al., 1997; Lee et al.,
1991; Shu et al., 2001; Witte et al., 1997; Wu et al.,
1996, 1998, 2002b; Yuan et al., 1995; Zheng
et al., 1999] tend to show lower rates of breast
cancer among those consuming higher amounts of
soy, although not all studies have shown statistical
significance. Breast cancer effects have recently been
reviewed in a meta-analysis by Trock et al. [2006],
which reported 30 and 23% lower breast cancer risk
estimates among premenopausal and postmenopausal women, respectively, and in our recent commentary [Wood & Messina, 2008], among others.
Interventional studies of the breast effects of soy
isoflavones in women are limited to short exposures
in women scheduled for breast surgery, nipple
aspirate studies, and mammographic density measurements. In general, the data from these studies
are equivocal. For example, Petrakis et al. [1996]
evaluated 24 pre- and postmenopausal women by
nipple aspirate and reported increased amounts of
aspirate fluid and epithelial hyperplasia in women
consuming soy. Unfortunately this study is difficult
to interpret in light of effects of time (nipple aspirate
fluid volume increased in all women across the study)
and low numbers of subjects. Another study, reported in part by McMichael-Phillips et al. [1998]
and subsequently in a final report by Hargreaves
et al. [1999], evaluated histologic markers in women
already scheduled for breast biopsy, who were given
a soy muffin delivering 45 mg of isoflavones for 2
weeks prior to the surgery. In the preliminary report
[McMichael-Phillips et al., 1998], an increase in cell
proliferation was shown, but this effect had disappeared at the time of the final report, although
increases in other estrogen-dependent markers such
as PS2 were found [Hargreaves et al., 1999]. This
study was compromised by the wide range of
diagnoses among women scheduled for surgery (from
benign fibrocystic disease to invasive carcinoma) and
the unavoidable lack of experimental control when
using human subjects. Perhaps the most intriguing
work to date is that of Maskarinec and Meng [2001],
who studied mammographic density. Greater mammographic density is clearly associated with a fourto six-fold increase in breast cancer risk [Boyd et al.,
1995]. Maskarinec found no effect of soy isoflavone
[Maskarinec et al., 2004]. Women of Caucasian
descent but not women of Asian descent who
reported greater lifetime soy consumption tended
to have higher mammographic percent densities.
This latter observation may indicate a physiologic,
genetic, or epigenetic acclimation to soy isoflavone
effects in populations consuming them over a
long period of time, a notion that harks back to
the multigenerational effect seen in the migration
Soy isoflavone effects on the lower reproductive
tract show a similar pattern. The observational
Am. J. Primatol.
724 / Cline and Wood
studies of soy consumption show a reduction in
endometrial cancer risk [Dai et al., 2007; Goodman
et al., 1997]. Short-term soy exposure has been
shown in several small studies to lack estrogen-like
effects [Murray et al., 2003; Nikander et al., 2005].
The only large intervention study to date was a
5-year study of postmenopausal women randomized
to either 150 mg of isoflavones (n 5 179) or placebo
(n 5 197) per day consumed as a tablet [Unfer et al.,
2004]. Endometrial histology was obtained by biopsy
at baseline, 30 months, and 5 years. At the study’s
end endometrial hyperplasia was found in 6/154
subjects in the treatment group and none in the
placebo group. Although the findings caused some
concern, the incidence of hyperplasia was comparable to controls in larger studies such as the
Women’s Health Initiative [Rossouw et al., 2002]
and the study was flawed by the lack of any
consideration of serum estrogens or isoflavone
measurements to confirm compliance.
The basis for soy isoflavone effects in human
subjects may lie in the modification of systemic
estrogen concentrations or other estrogen-related
mechanisms. Asian women who consume soy and
have low risk for breast and endometrial cancer have
lower serum estrogens relative to high-risk Caucasian women [Wu et al., 2002a,b]; however, Asian
women who have migrated to the United States have
estrogen levels comparable to American women
[Goodman et al., 1997; Probst-Hensch et al., 2000].
Cassidy et al. [1994] first reported effects of dietary
soy (containing 45 mg isoflavones/day) on endogenous pituitary and ovarian hormones in women,
demonstrating lowering of the mid-cycle LH and
FSH, lower estradiol, and lengthening of the follicular phase of the menstrual cycle. Soy-associated
reductions in sex steroids in women have since been
found in several studies [Lu et al., 2000, 2001; Wu
et al., 2000; Xu et al., 2000]. Some investigators have
found no effect of dietary soy consumption on sex
steroids [Martini et al., 1999], but the weight of
evidence is in the direction of a small suppression of
hypothalamo-pituitary gonadal function. Lu et al.
[2000], in tightly controlled dietary studies of soy
effects on premenopausal women, found that dietary
soy containing approximately 150 mg of isoflavone/
day reduced serum progesterone concentrations by
45% and estradiol concentrations by 25%. Isoflavonedepleted supplements also reduced progesterone by
33% and estradiol by 25% [Lu et al., 2001] indicating
that other components of soy may also modulate
ovarian steroidogenesis. In a longer (7-month) but
less tightly controlled study, Wu et al. [2000] found
that dietary soy consumption lowered luteal-phase
estradiol (17%) but not progesterone, and that this
effect was only evident in Asian women. Soy
consumption has also been associated with lowering
of estrone in postmenopausal women in Shanghai
[Wu et al., 2002a]. Other investigators have shown
Am. J. Primatol.
that diet can affect pubertal sex steroid levels in girls
[Dorgan et al., 2003].
There are many mechanistic reasons why soy
isoflavones may antagonize estrogenic effects, including a variety of antiproliferative effects, modulation of steroid hormone metabolizing enzymes and
binding proteins, induction of apoptosis, and inhibition of angiogenesis [Wood et al., 2002]. In addition,
dietary soy or genistein consumption early in life
protects the mammary gland of rodents by inducing
differentiation of cancer-susceptible terminal end
buds within the mammary gland [Lamartiniere,
2000; Lamartiniere et al., 1998; Warri et al., 2008].
The most extensively studied isoflavone is
genistein, which can bind to and mediate transcription by estrogen receptors a and b [Kuiper et al.,
1998; Miksicek, 1994; Morito et al., 2002]. Several
investigators have shown that in the absence of
estrogen, isoflavones have weak estrogenic effects,
whereas in the presence of estrogen, they may exert
an antagonistic effect [Folman & Pope, 1966;
Messina et al., 1994], consistent with our own
observations in rodents [Cline et al., 1998b] and
female macaques [Foth & Cline, 1998; Wood et al.,
2006b]. Some investigators have shown antagonism
of estrogen-induced proliferation of estrogen-dependent MCF-7 breast cancer cells at physiologic doses
[Imhof et al., 2008]. Thus there may be competitive,
estrogen receptor-mediated effects. However, it may
be that the weak estrogenicity of genistein has little
to do with its anticancer effect [Barnes, 1995]. At
higher doses (410 mM), genistein has antiproliferative effects in MCF-7 breast cancer cells regardless of
their estrogen receptor positivity [Peterson &
Barnes, 1991; Tanos et al., 2002; Wang et al.,
1996]. This high-dose effect is therefore presumably
not dependent on the receptor, and perhaps is
mediated by genistein’s potent inhibition of tyrosine
kinase activity [Akiyama et al., 1987] or by an
epigenetic differentiating effect [Dolinoy et al.,
2006]. Genistein is also an inhibitor of DNA
topoisomerase [Constantinou & Huberman, 1995],
which may be an integral part of its differentiationinducing properties. It is also an antioxidant [Wei
et al., 1995] and induces apoptosis in breast cancer
cell lines in vitro [Kiguchi et al., 1994]. Furthermore,
genistein has antiproliferative and antiangiogenic
effects on vascular endothelial cells in vitro [Fotsis
et al., 1995] and in tumor models [Buchler et al.,
2004; Kim, 2003; Li & Sarkar, 2002; Myoung et al.,
2003; Wietrzyk et al., 2005], leading to the hypothesis that its antiangiogenic properties may be
responsible for the relatively indolent nature
of breast carcinomas in Asian women. Genistein
also induces expression of the inhibitory growth
Estrogen/Isoflavone Interactions in Macaques / 725
factor transforming growth factor b, which
diminishes epithelial cell proliferation in the breast
[Sathyamoorthy et al., 1998] and endometrium.
Studies evaluating adolescent dietary intakes in
human subjects [Shu et al., 2001; Wu et al., 2002b]
show that early exposure to dietary soy (before or
during pubertal development) produces the clearest
protective effect against breast cancer. The observations of Lamartiniere [2000] and Lamartiniere et al.
[1998] show that in rodents the critical period of
protective soy or soy isoflavone exposure is during
early development of the breast. In contrast to an
early protective effect, pre-existing neoplasms are
promoted. The work of Allred et al. [2004] and Hsieh
et al. [1998] has shown that once neoplasms are
present, genistein exposure can increase the proliferation of xenografted or chemically induced mammary cancers in rodents. Hilakivi-Clarke et al. [2002]
have shown that in utero exposure, in contrast to
neonatal exposure, increases the numbers of undifferentiated terminal end buds in the mammary
glands of offspring in rats, thus increasing susceptibility to mammary cancer induction. Therefore, it
appears that timing of exposure is a critical determinant of isoflavone effects on breast cancer risk
[Warri et al., 2008].
The soy isoflavone genistein is a powerful
modulator of DNA methylation in utero, leading to
altered phenotypes in mice. Dolinoy et al. [2006] in a
landmark study demonstrated that in utero exposure
to dietary genistein could modify coat color in mice
by methylation of a regulatory sequence governing
expression of the Agouti coat color gene. This study
demonstrated that methylation patterns in a retrotransposal element in the promoter of Agouti were
hypermethylated at six CpG sites in offspring. These
methylation patterns persisted into adulthood. The
effects of this hypermethylation not only altered coat
color but also caused lower ectopic Agouti expression,
which effectively protected the offspring from adult
obesity. Furthermore, exposure of rats to isoflavones
during the development of GnRH-producing neurons
permanently alters gonadotropin secretion [Bateman
& Patisaul, 2008]. On the basis of examples such as
this, we believe that soy isoflavones have a high
potential as modulators in the ‘‘fetal basis of adult
disease’’ or ‘‘Barker hypothesis’’ [Barker, 1992;
Barker et al., 2005], which postulates that nutrition
and/or environmental factors during prenatal and
early development influence cellular plasticity,
thereby altering future susceptibility to disease.
Our current work is focused on the potential for
such effects of dietary soy consumption during the
pubertal transition in macaques (Cline, NIH R01
Why Nonhuman Primates?
Old-World monkeys have well-documented similarities to women in terms of reproductive physiology.
Endometrial and ovarian physiologies have long been
regarded as nearly identical to that of women; only
Old-World primates and great apes menstruate [Attia,
1998; Bellino & Wise, 2003; Hodgen et al., 1977], and
there are many more subtle similarities in anatomy,
development, peripheral steroid hormone metabolism,
sex steroid receptor expression, and other features
[Cline, 2007; Cline et al., 1996a, 1998b, 2002, 2007,
2008; Kaiserman-Abramof & Padykula, 1989; Mahoney, 1970; Speert, 1948; Wood et al., 2006a]. These
features are not shared by rodent models. Although
laboratory rodents provide the advantages of ease of
use, short life span, and the potential for genetic
manipulation, they differ substantially from primates
in terms of reproductive biology [Everett, 1989] and
mammary gland physiology. The exogenous and
endogenous mouse mammary tumor viruses,
although experimentally useful [Medina, 2008], have
no counterpart in human or nonhuman primates.
Prolactin receptor knockout mice have a failure of
mammary gland development, along with a variety of
other abnormalities [Kelly et al., 2001]. In contrast,
prolactin is not an obligate component of mammary
growth and development in macaques, although it is
required for lactation [Kleinberg et al., 1985]. Rodents
do not menstruate, and reproduction differs in that
the formation of the corpus luteum is dependent on
coitus in rodents but not in primates [Freeman, 1994;
Weinbauer et al., 2008]. In rodents reproductive
senescence is characterized not by menopause but
by ‘‘persistent estrus’’ [Freeman, 1994; Westwood,
2007], which differs markedly from menopause as
observed in human beings and Old-World monkeys
[Kavanagh, 2005]. We have found in the process of
sequencing coding portions of monkey mRNA transcripts for steroidogenic enzymes that there is a high
degree of similarity (95–97%) between monkey and
human DNA sequences [Scott et al., 2008; Wood et al.,
2006b, 2007], compared with a much lower (50–80%)
similarity for rodents. The enzymatic ‘‘machinery’’ of
peripheral sex steroid metabolism in macaques is
similar to that of women [Soderqvist et al., 1994,
1998], and the full complement of aromatase, 17-bhydroxysteroid dehydrogenases, sulfatases, and other
metabolic pathways relevant to intratissue sex steroid
metabolism are present [Martel et al., 1994; Scott
et al., 2008; Wood et al., 2007] and are modified in
adult animals by dietary soy isoflavone exposure
[Scott et al., 2008; Wood et al., 2007].
Hormones and Cancer Risk
We have shown that the primate model of breast
and endometrial regulation provides a unique degree
Am. J. Primatol.
726 / Cline and Wood
of similarity to human breast and endometrium. Our
results with respect to breast proliferation as a
surrogate marker of cancer risk demonstrated that
the progestin medroxyprogesterone acetate augmented estrogen-induced proliferation [Cline et al.,
1998a]. We believe that this finding predicted the
results of several recent large trials in women
indicating that the use of progestins in HRT may
increase breast cancer risk [Beral, 2003; Rossouw
et al., 1999; Schairer et al., 2000].
Evidence for Estrogen/Isoflavone Interactions
We have shown that soy isoflavones are not
estrogenic alone at up to 10 times dietary levels
(500 mg/person/day equivalent compared with
50 mg/person/day in a high-soy Asian diet) in
cynomolgus monkeys [Wood et al., 2006c]. We have
also shown that at much lower concentrations
(120 mg/person/day equivalent) they reduce estrogen-induced proliferative responses of the breast and
endometrium [Wood et al., 2006b]. This effect may
be mediated through estrogen receptor interactions
and/or modulation of endogenous estrogen metabolism. We have shown in monkeys that there are
interactive effects of soy with both endogenous [Scott
et al., 2008; Wood et al., 2002] and exogenous [Foth
& Cline, 1998; Wood et al., 2006b] estrogens in the
postmenopausal period. There is an inverse association between serum estrone and serum isoflavone
concentrations [Wood et al., 2006b], and long-term
changes in estrogen metabolism induced by prior
hormonal and soy treatments [Scott et al., 2008;
Wood et al., 2007]. Figure 2 shows the inverse
relationship between endogenous estrogens and soy
isoflavones in the serum of cynomolgus macaques
consuming a soy isoflavone-rich diet providing
129 mg/woman/day equivalent of total isoflavones
[Wood et al., 2004]. In our studies of combined
exogenous estradiol and dietary isoflavones, we
found that dietary isoflavone in the high dietary
range could reduce circulating [Wood et al., 2006b]
and intrabreast [Wood et al., 2007] estradiol concentrations in adult cynomolgus monkeys, and that
lowered circulating estradiol was associated with a
decrease in tissue proliferation as measured by Ki67
expression in breast epithelium and endometrial size
by ultrasound (Fig. 3).
Putative Soy-Derived Selective Estrogens
Our findings of dose-dependent estrogen antagonistic effects of soy isoflavones on systemic estrogen
concentrations and tissue responses indicate that
there are ‘‘anti-estrogens’’ or modulators of mammalian estrogen effects among the isoflavones. Given the
well-documented estrogen-like beneficial effect of
isoflavones on cardiovascular disease risk [Food and
Drug Administration, 1999] and the lack of estrogen
agonist effects in primates, we have sought to identify
such selective agonists. Glyceollins are a recently
discovered class of phytoalexin compounds produced
from isoflavones by soybean plants under stressed
conditions. Glyceollins do not produce estrogen-like
uterine weight gains in mice but do reduce the
growth of estrogen-dependent MCF-7 breast cancer
xenografts [Burow et al., 2001]. In our studies of
glyceollins administered along with estradiol to
postmenopausal cynomolgus monkeys, we found a
distinct blunting of the estrogen-induced proliferative
and transcriptional response in the breast but not in
the lower reproductive system [Wood et al., 2006d].
Another potential selective estrogen is equol.
This compound is derived by bacterial metabolism
from the native soy isoflavone daidzein, and is
associated with reduced risk of hormone-dependent
cancers. Only about 30% of human subjects produce
equol after soy isoflavone consumption [Duncan
et al., 2000]. As essentially all macaques are equol
producers [Wood et al, 2006b], they mimic this
subpopulation of human subjects. Human equol
producers have lower-risk estrogen-metabolic
profiles, skewed more toward the production of
2-hydroxy estrogen metabolites, which may be
Serum Iso
oflavones (n
Serum Estrone (ng/mL)
Fig. 2. Inverse relationship between dietary soy isoflavone concentrations in serum and endogenous serum estrone in 60 female
ovariectomized control cynomolgus macaques. R 5 0.37, P 5 0.0048.
Am. J. Primatol.
Estrogen/Isoflavone Interactions in Macaques / 727
Fig. 3. Antagonistic effects of soy isoflavones on breast proliferation and uterine size in either low or high E2 environment. Proliferation
was measured by immunohistochemical expression of the proliferation marker Ki67 in breast lobular and ductal epithelium and uterine
area was determined by transabdominal ultrasound. The 240 mg isoflavone dose resulted in significantly lower mammary epithelial Ki67
expression and uterine area in the high-estrogen (E2) environment (n 5 29–31 per diet). Horizontal lines, washout values for uterine size
measured 1 month after discontinuing treatment. (a) Po0.05 compared with low E2 control; (b) Po0.05 compared with high E2 control.
Bars, SE. From Wood et al. [2006b], with permission.
cancer preventive [Duncan et al., 2000]. It is
currently unclear whether equol is an effector or a
marker of a particular estrogen-metabolic phenotype
[Xu et al., 2000].
Soy isoflavone exposure of rodents alters the
onset of puberty; work from the National Toxicology
Program indicates an acceleration of puberty as
assessed by vaginal opening in rats [Casanova et al.,
1999; Delclos et al., 2001, 2007]. The estrogenic
effects of other dietary phytoestrogens are well
known; for example, ‘‘clover disease,’’ a syndrome
of reproductive disruption in sheep, is caused by
grazing on pastures rich in coumestrol [Adams, 1995;
Bennets, 1946]. These female reproductive tract
effects include an increase in thickness and keratinization of vaginal epithelium, enlarged cervix,
increased uterine weight, and endometrial hyperplasia, all of which are similar to the changes induced by
steroidal estrogens [Adams, 1995]. Adverse effects
have been reported in carnivores as well; captive
cheetahs experienced a syndrome of hepatic venoocclusive disease attributed to excessive phytoestrogen exposure from soy-based diets [Setchell et al.,
Am. J. Primatol.
728 / Cline and Wood
1987]. Although there is some evidence that isoflavones alter early development in male marmosets
[Sharpe et al., 2002], there is no evidence for longterm adverse effects in male or female primates.
Interestingly, most primates are maintained on
‘‘monkey chow,’’ which contains highly variable but
generally bioactive levels of isoflavones, as our
colleagues have recently reported [Stroud et al.,
2006]; levels of exposure were similar to those used
for our experimental isoflavone trials [Wood et al.,
2004]. These levels are sufficient to alter the
behavior of male cynomolgus macaques, resulting
in increased aggressive and decreased affiliative
behavior [Simon et al., 2004]. It may be that the
‘‘standard’’ colony-reared nonhuman primate has an
abnormal pubertal onset as a result of this exposure.
The potential for such endocrine disrupting effects of
a high-isoflavone soy diet has long been recognized in
rodent studies [Boettger-Tong et al., 1998; Thigpen
et al., 1999]. Regardless of whether isoflavoneexposed or isoflavone-free is the more physiologic
situation, primatologists should be aware of the
potential for confounding effects of dietary isoflavones on reproductive development and other
aspects of experimental work.
Adams NR. 1995. Organizational and activational effects of
phytoestrogens on the reproductive tract of the ewe. Proc
Soc Exp Biol Med 208:87–91.
Akiyama T, Ishida J, Ogawara H, Watanabe S, Itoh N,
Shibuya M, Fukami Y. 1987. Genistein, a specific inhibitor
of tyrosin-specific protein kinases. J Biol Chem 262:
Allred CD, Allred KF, Ju YH, Clausen LM, Doerge DR,
Schantz SL, Korol DL, Wallig MA, Helferich WG. 2004.
Dietary genistein results in larger MNU-induced, estrogendependent mammary tumors following ovariectomy of
Sprague–Dawley rats. Carcinogenesis 25:211–218.
Attia MA. 1998. Cyclic changes in genital organs and vaginal
cytology in cynomolgus monkeys (Macaca fascicularis).
Dtsch Tierarztl Wochenschr 105:399–404.
Barker DJB, editor. 1992. Fetal and infant origins of adult
disease. London: BMJ Publishing Group.
Barker DJP, Osmond C, Forsen TJ, Kajantie E, Eriksson JG.
2005. Trajectories of growth among children who have
coronary events as adults. N Engl J Med 353:1802–1809.
Barnes S. 1995. Effect of genistein on in vitro and in vivo
models of cancer. J Nutr 125:777S–783S.
Bateman HL, Patisaul HB. 2008. Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased
GnRH activation and kisspeptin fiber density in the
hypothalamus. Neurotoxicology 29:988–997.
Bellino FL, Wise PM. 2003. Nonhuman primate models of
menopause workshop. Biol Reprod 68:10–18.
Bennetts HW, Underwood EJ, Shier FL. 1946. A specific
breeding problem of sheep on subterranean clover pastures
in Western Australia. Aust J Agric Res 22:131–138.
Beral V. 2003. Breast cancer and hormone-replacement
therapy in the Million Women Study. Lancet 362:419–427.
Boettger-Tong H, Murthy L, Chiappetta C, Kirkland JL,
Goodwin B, Adlercreutz H, Stancel GM, Mäkelä S. 1998. A
case of a laboratory animal feed with high estrogenic activity
Am. J. Primatol.
and its impact on in vivo responses to exogenously administered estrogens. Environ Health Perspect 106:369–373.
Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB,
Lockwood GA, Tritchler DL, Yaffe MJ. 1995. Quantitative
classification of mammographic densities and breast cancer
risk: results from the Canadian National Breast Screening
Study. J Natl Cancer Inst 87:670–675.
Buchler P, Reber HA, Buchler MW, Friess H, Lavey RS,
Hines OJ. 2004. Antiangiogenic activity of genistein in
pancreatic carcinoma cells is mediated by the inhibition of
hypoxia-inducible factor-1 and the down-regulation of
VEGF gene expression. Cancer 100:201–210.
Burow ME, Boue SM, Collins-Burow BM, Melnik LI, Duong
BN, Carter-Wientjes CH, Li S, Wiese TE, Cleveland TE,
McLachlan JA. 2001. Phytochemical glyceollins, isolated
from soy, mediate antihormonal effects through estrogen
receptor alpha and beta. J Clin Endocrinol Metab
Casanova M, You L, Gaido KW, Archibeque-Engle S,
Janszen DB, Heck HA. 1999. Developmental effects of
dietary phytoestrogens in Sprague–Dawley rats and interactions of genistein and daidzein with rat estrogen receptors
alpha and beta in vitro. Toxicol Sci 51:236–244.
Cassidy A, Bingham S, Setchell KD. 1994. Biological effects of
a diet of soy protein rich in isoflavones on the menstrual
cycle of premenopausal women. Am J Clin Nutr 60:333–340.
Cline JM. 2007. Assessing the mammary gland of nonhuman
primates: effects of endogenous hormones and exogenous
hormonal agents and growth factors. Birth Defects Res B
Dev Reprod Toxicol 80:126–146.
Cline JM, Soderqvist G, von Schoultz E, Skoog L,
von Schoultz B. 1996a. Effects of hormone replacement
therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 174:93–100.
Cline JM, Paschold JC, Anthony MC, Obasanjo IO,
Adams MR. 1996b. Effects of hormonal therapies and
dietary soy phytoestrogens on vaginal cytology in surgically
postmenopausal macaques. Fertil Steril 65:1031–1035.
Cline JM, Soderqvist G, Skoog L, von Schoultz B. 1998a.
Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques.
Breast Cancer Res Treat 48:221–229.
Cline JM, Davis VL, Hughes CL. 1998b. Dietary soy has dosedependent agonist/antagonist effects on the mammary glands
and uteri of estrogen-treated rats. Proceedings of the ILSI
conference on human diet and endocrine modulation.
Cline JM, Register TC, Clarkson TB. 2002. Comparative
effects of tibolone and conjugated equine estrogens with
and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys. Menopause
Cline JM, Wood CE, Vidal J, Tarara R, Buse E, Weinbauer G,
de Rijk E, van Esch E. 2008. Selected background findings of
the female reproductive system in macaques. Toxicol Pathol
Constantinou A, Huberman E. 1995. Genistein as an inducer
of tumor cell differentiation: possible mechanisms of action.
Proc Soc Exp Biol Med 208:109–115.
Dai Q, Franke AA, Jin F, Shu XO, Hebert JR, Custer LJ,
Cheng J, Gao YT, Zheng W. 2002. Urinary excretion of
phytoestrogens and risk of breast cancer among Chinese
women in Shanghai. Cancer Epidemiol Biomarkers Prev
Dai Q, Xu WH, Long JR, Courtney R, Xiang YB, Cai Q,
Cheng J, Zheng W, Shu XO. 2007. Interaction of soy
and 17beta-HSD1 gene polymorphisms in the risk of
endometrial cancer. Pharmacogenet Genomics 17:
Delclos KB, Newbold R. 2007. NTP toxicity report of
reproductive dose range-finding study of genistein (CAS
Estrogen/Isoflavone Interactions in Macaques / 729
No. 446-72-0) administered in feed to Sprague–Dawley rats.
Toxic Rep Ser 79:1-C2.
Delclos KB, Bucci TJ, Lomax LG, Latendresse JR,
Warbritton A, Weis CC, Newbold RR. 2001. Effects of
dietary genistein exposure during development on male and
female CD (Sprague–Dawley) rats. Reprod Toxicol
den Tonkelaar I, Keinan-Boker L, Veer PV, Arts CJ,
Adlercreutz H, Thijssen JH, Peeters PH. 2001. Urinary
phytoestrogens and postmenopausal breast cancer risk.
Cancer Epidemiol Biomarkers Prev 10:223–228.
Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. 2006.
Maternal genistein alters coat color and protects Avy mouse
offspring from obesity by modifying the fetal epigenome.
Environ Health Perspect 114:567–572.
Dorgan JF, Hunsberger SA, McMahon RP, Kwiterovich PO,
Lauer RM, Van Horn L, Lasser LN, Stevens VJ,
Friedman LA, Yanovski JA, Greenhut SF, Chandler DW,
Franklin FA, Barton BA, Buckman DW, Snetselaar LG,
Patterson BH, Schatzkin A, Taylor PR. 2003. Diet and sex
hormones in girls: findings from a randomized controlled
clinical trial. J Natl Cancer Inst 95:132–141.
Duncan AM, Merz-Demlow BE, Xu X, Phipps WR, Kurzer MS.
2000. Premenopausal equol excretors show plasma hormone
profiles associated with lowered risk of breast cancer.
Cancer Epidemiol Biomarkers Prev 9:581–586.
Dunn JE. 1977. Breast cancer among American Japanese in
the San Francisco Bay area. Natl Cancer Inst Monogr
Everett JW. 1989. Neurobiology of reproduction in the female
rat. A fifty-year perspective. Monogr Endocrinol 32:1–133.
Folman Y, Pope GS. 1966. The interaction in the immature
mouse of potent oestrogens with coumestrol, genistein and
other utero-vaginotrophic compounds of low potency.
J Endocrinol 34:215–225.
Food and Drug Administration. 1999. Food labeling: health
claims; soy protein and coronary heart disease. Fed Regist
Foth D, Cline JM. 1998. Effects of mammalian and plant
estrogens on mammary glands and uteri of macaques. Am J
Clin Nutr 68:1413S–1417S.
Fotsis T, Pepper M, Adlercreutz H, Hase T, Montesano R,
Schweigerer L. 1995. Genistein, a dietary ingested isoflavonoid, inhibits cell proliferation and in vitro angiogenesis.
J Nutr 125:790S–797S.
Freeman ME. 1994. The neuroendocrine control of the ovarian
cycle of the rat. In: Knobil E, Neill JD, editors. The
physiology of reproduction, 2nd ed. New York: Raven Press.
Goodman MT, Wilkens LR, Hankin JH, Lyu LC, Wu AH,
Kolonel LN. 1997. Association of soy and fiber consumption
with the risk of endometrial cancer. Am J Epidemiol
Greenstein J, Kushi L, Zheng W, Fee R, Campbell D, Sellers T.
1996. Risk of breast cancer associated with intake of specific
foods and food groups. Am J Epidemiol 143:S36.
Hargreaves DF, Potten CS, Harding C, Shaw LE, Morton MS,
Roberts SA, Howell A, Bundred NJ. 1999. Two-week dietary
soy supplementation has an estrogenic effect on normal
premenopausal breast. J Clin Endocrinol Metab 84:
Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S,
Helferich W, Lippman ME, Clarke R. 2002. Dietary
modulation of pregnancy estrogen levels and breast cancer
risk among female rat offspring. Clin Cancer Res
Hirayama T. 1990. A large scale cohort study on the effect of
life styles on the risk of cancer by each site. Gan No Rinsho
Spec No: 233-42.
Hirose K, Tajima K, Hamajima N, Inoue M, Takezaki T,
Kuroishi T, Yoshida M, Tokudome S. 1995. A large-scale,
hospital-based case–control study of risk factors of breast
cancer according to menopausal status. Jpn J Cancer Res
Hodgen GD, Goodman AL, O’Connor A, Johnson DK. 1977.
Menopause in rhesus monkeys: model for study of disorders
in the human climacteric. Am J Obstet Gynecol
Horn-Ross PL, John EM, Lee M, Stewart SL, Koo J,
Sakoda LC, Shiau AC, Goldstein J, Davis P, Perez-Stable EJ.
2001. Phytoestrogen consumption and breast cancer risk in
a multiethnic population: the Bay Area Breast Cancer
Study. Am J Epidemiol 154:434–441.
Horn-Ross PL, Hoggatt KJ, West DW, Krone MR, Stewart SL,
Anton H, Bernstein CL, Deapen D, Peel D, Pinder R,
Reynolds P, Ross RK, Wright W, Ziogas A. 2002. Recent diet
and breast cancer risk: the California Teachers Study
(USA). Cancer Causes Control 13:407–415.
Hsieh CY, Santell RC, Haslam SZ, Helferich WG. 1998.
Estrogenic effects of genistein on the growth of estrogen
receptor-positive human breast cancer (MCF-7) cells in vitro
and in vivo. Cancer Res 58:3833–3838.
Imhof M, Molzer S, Imhof M. 2008. Effects of soy isoflavones
on 17beta-estradiol-induced proliferation of MCF-7 breast
cancer cells. Toxicol In Vitro 22:1452–1460.
Ingram D, Sanders K, Kolybaba M, Lopez D. 1997. Case–
control study of phyto-oestrogens and breast cancer. Lancet
Kaiserman-Abramof I, Padykula H. 1989. Ultrastructural
epithelial zonation of the primate endometrium (rhesus
monkey). Am J Anat 184:13–30.
Kavanagh K, Koudy Williams J, Wagner JD. 2005. Naturally
occurring menopause in cynomolgus monkeys: changes in
hormone, lipid, and carbohydrate measures with hormonal
status. J Med Primatol 34:171–177.
Kelly PA, Binart N, Lucas B, Bouchard B, Goffin V. 2001.
Implications of multiple phenotypes observed in prolactin
receptor knockout mice. Front Neuroendocrinol 22:140–145.
Kiguchi K, Glesne D, Chubb CH, Fujiki H, Huberman E.
1994. Differential induction of apoptosis in human
breast tumor cells by okadaic acid and related inhibitors
of protein phosphatases 1 and 2A. Cell Growth Differ
Kim MH. 2003. Flavonoids inhibit VEGF/bFGF-induced
angiogenesis in vitro by inhibiting the matrix-degrading
proteases. J Cell Biochem 89:529–538.
Kleinberg DL, Niemann W, Flamm E, Cooper P, Babitsky G,
Valensi Q. 1985. Primate mammary development. Effects of
hypophysectomy, prolactin inhibition, and growth hormone
administration. J Clin Invest 75:1943–1950.
Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH,
van der Saag PT, van der Burg B, Gustafsson JA. 1998.
Interaction of estrogenic chemicals and phytoestrogens with
estrogen receptor beta. Endocrinology 139:4252–4263.
Lamartiniere CA. 2000. Protection against breast cancer with
genistein: a component of soy. Am J Clin Nutr 71:
1705S–1707S; discussion 1708S–1709S.
Lamartiniere CA, Murrill WB, Manzolillo PA, Zhang JX,
Barnes S, Zhang X, Wei H, Brown NM. 1998. Genistein
alters the ontogeny of mammary gland development and
protects against chemically-induced mammary cancer in
rats. Proc Soc Exp Biol Med 217:358–364.
Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. 1991.
Dietary effects on breast-cancer risk in Singapore. Lancet
Li Y, Sarkar FH. 2002. Down-regulation of invasion and
angiogenesis-related genes identified by cDNA microarray
analysis of PC3 prostate cancer cells treated with genistein.
Cancer Lett 186:157–164.
Lu LJ, Anderson KE, Grady JJ, Kohen F, Nagamani M. 2000.
Decreased ovarian hormones during a soya diet: implications
for breast cancer prevention. Cancer Res 60:4112–4121.
Am. J. Primatol.
730 / Cline and Wood
Lu LJ, Anderson KE, Grady JJ, Nagamani M. 2001. Effects of
an isoflavone-free soy diet on ovarian hormones in premenopausal women. J Clin Endocrinol Metab 86:3045–3052.
Mahoney C. 1970. A study of the menstrual cycle in Macaca
irus with special reference to the detection of ovulation.
J Reprod Fertil 21:153–163.
Martel C, Melner MH, Gagne D, Simard J, Labrie F. 1994.
Widespread tissue distribution of steroid sulfatase, 3 betahydroxysteroid dehydrogenase/delta 5-delta 4 isomerase 3
beta-HSD, 17 beta-HSD 5 alpha-reductase and aromatase
activities in the rhesus monkey. Mol Cell Endocrinol
Martini MC, Dancisak BB, Haggans CJ, Thomas W, Slavin JL.
1999. Effects of soy intake on sex hormone metabolism in
premenopausal women. Nutr Cancer 34:133–139.
Maskarinec G, Meng L. 2001. An investigation of soy intake
and mammographic characteristics in Hawaii. Breast
Cancer Res 3:134–141.
Maskarinec G, Takata Y, Franke AA, Williams AE,
Murphy SP. 2004. A 2-year soy intervention in premenopausal women does not change mammographic densities.
J Nutr 134:3089–3094.
McMichael-Phillips DF, Harding C, Morton M, Roberts SA,
Howell A, Potten CS, Bundred NJ. 1998. Effects of soyprotein supplementation on epithelial proliferation in the
histologically normal human breast. Am J Clin Nutr
Medina D. 2008. Premalignant and malignant mammary
lesions induced by MMTV and chemical carcinogens.
J Mammary Gland Biol Neoplasia 13:271–277.
Messina MJ, Persky V, Setchell KD, Barnes S. 1994. Soy
intake and cancer risk: a review of the in vitro and in vivo
data. Nutr Cancer 21:113–131.
Miksicek RJ. 1994. Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human
estrogen receptor. J Steroid Biochem Mol Biol 49:153–160.
Morito K, Aomori T, Hirose T, Kinjo J, Hasegawa J, Ogawa S,
Inoue S, Muramatsu M, Masamune Y. 2002. Interaction of
phytoestrogens with estrogen receptors alpha and beta (II).
Biol Pharm Bull 25:48–52.
Murray MJ, Meyer WR, Lessey BA, Oi RH, DeWire RE,
Fritz MA. 2003. Soy protein isolate with isoflavones does not
prevent estradiol-induced endometrial hyperplasia in
postmenopausal women: a pilot trial. Menopause 10:
Myoung H, Hong SP, Yun PY, Lee JH, Kim MJ. 2003. Anticancer effect of genistein in oral squamous cell carcinoma
with respect to angiogenesis and in vitro invasion. Cancer
Sci 94:215–220.
Nikander E, Rutanen EM, Nieminen P, Wahlström T,
Ylikorkala O, Tiitinen A. 2005. Lack of effect of isoflavonoids on the vagina and endometrium in postmenopausal
women. Fertil Steril 83:137–142.
Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay J, Powell J,
editors. 1992. IARC scientific publication no. 120; cancer
incidence in five continents. Lyon: International Agency for
Research on Cancer.
Peterson G, Barnes S. 1991. Genistein inhibition of the growth
of human breast cancer cells: independence from estrogen
receptors and the multi-drug resistance gene. Biochem
Biophys Res Commun 179:661–667.
Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J,
Lee MM, Miike R, Kirk M, Coward L. 1996. Stimulatory
influence of soy protein isolate on breast secretion in preand postmenopausal women. Cancer Epidemiol Biomarkers
Prev 5:785–794.
Probst-Hensch NM, Pike MC, Mckean-Cowdin R,
Stanczyk FZ, Kolonel LN, Henderson BE. 2000. Ethnic
differences in post-menopausal plasma oestrogen levels:
high oestrone levels in Japanese-American women despite
low weight. Br J Cancer 82:1867–1870.
Am. J. Primatol.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ,
Kooperberg C, Stefanick ML, Jackson RD, Beresford SA,
Howard BV, Johnson KC, Kotchen JM, Ockene J. 2002.
Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the
Women’s Health Initiative randomized controlled trial.
J Am Med Assoc 288:321–333.
Sathyamoorthy N, Gilsdorf JS, Wang TT. 1998. Differential
effect of genistein on transforming growth factor beta 1
expression in normal and malignant mammary epithelial
cells. Anticancer Res 18:2449–2453.
Schairer CP, Lubin LP, Troisi RS, Sturgeon SD, Brinton LP,
Hoover RMD. 2000. Menopausal estrogen and estrogen–
progestin replacement therapy and breast cancer risk. J Am
Med Assoc 283:485–491.
Scott LM, Xu X, Veenstra TD, Tooze JA, Wood CE,
Register TC, Kock ND, Cline JM. 2008. Past oral contraceptive
use and current dietary soy isoflavones influence estrogen
metabolism in postmenopausal monkeys (Macaca fascicularis). Cancer Epidemiol Biomarkers Prev 17:2594–2602.
Setchell KD, Gosselin SJ, Welsh MB, Johnston JO, Balistreri
WF, Kramer LW, Dresser BL, Tarr MJ. 1987. Dietary
estrogens—a probable cause of infertility and liver disease
in captive cheetahs. Gastroenterology 93:225–233.
Sharpe RM, Martin B, Morris K, Greig I, McKinnell C,
McNeilly AS, Walker M. 2002. Infant feeding with soy
formula milk: effects on the testis and on blood testosterone
levels in marmoset monkeys during the period of neonatal
testicular activity. Hum Reprod 17:1692–1703.
Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE,
Mack TM. 1991. Cancers of the prostate and breast among
Japanese and white immigrants in Los Angeles County. Br J
Cancer 63:963–966.
Shu XO, Jin F, Dai Q, Wen W, Potter JD, Kushi LH, Ruan Z,
Gao YT, Zheng W. 2001. Soyfood intake during adolescence
and subsequent risk of breast cancer among Chinese
women. Cancer Epidemiol Biomarkers Prev 10:483–488.
Simon NG, Kaplan JR, Hu S, Register TC, Adams MR. 2004.
Increased aggressive behavior and decreased affiliative
behavior in adult male monkeys after long-term consumption of diets rich in soy protein and isoflavones. Horm Behav
Söderqvist G, Olsson H, Wilking N, von Schoultz B,
Carlstrom K. 1994. Metabolism of estrone sulfate by normal
breast tissue: influence of menopausal status and oral
contraceptives. J Steroid Biochem Mol Biol 48:221–224.
Söderqvist G, Poutanen M, Wickman M, von Schoultz B,
Skoog L, Vihko R. 1998. 17Beta-hydroxysteroid dehydrogenase type 1 in normal breast tissue during the menstrual
cycle and hormonal contraception. J Clin Endocrinol Metab
Soyatech Inc. 2008. U.S. retail sales of soy foods 1992–2002.
soychart.html. 2003. Food and Drug Administration.
Accessed on 10/19/2008.
Soy Foods Association of North America. 2008. Soyfood sales &
trends. Availabe from:
sales-and-trends/. Accessed on 10/19/2008.
Speert H. 1948. The normal and experimental development of
the mammary gland of the rhesus monkey with some
pathologic correlations. Contrib Embryol (Carnegie Inst
Wash) 32:9–65.
Stanford JL, Herrinton LJ, Schwartz SM, Weiss NS. 1995.
Breast cancer incidence in Asian migrants to the United
States and their descendants. Epidemiology 6:181–183.
Stroud FC, Appt SE, Wilson ME, Franke AA, Adams MR,
Kaplan JR. 2006. Concentrations of isoflavones in macaques
consuming standard laboratory monkey diet. J Am Assoc
Lab Anim Sci 45:20–23.
Tanos V, Brzezinski A, Drize O, Strauss N, Peretz T. 2002.
Synergistic inhibitory effects of genistein and tamoxifen on
Estrogen/Isoflavone Interactions in Macaques / 731
human dysplastic and malignant epithelial breast cells in
vitro. Eur J Obstet Gynecol Reprod Biol 102:188–194.
Thigpen JE, Setchell KD, Ahlmark KB, Locklear J, Spahr T,
Caviness GF, Goelz MF, Haseman JK, Newbold RR,
Forsythe DB. 1999. Phytoestrogen content of purified, openand closed-formula laboratory animal diets. Lab Anim Sci
Trock BJ, Hilakivi-Clarke L, Clarke R. 2006. Meta-analysis of
soy intake and breast cancer risk. J Natl Cancer Inst
Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Di Renzo
GC. 2004. Endometrial effects of long-term treatment with
phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril 82:145–148.
Wang TT, Sathyamoorthy N, Phang JM. 1996. Molecular
effects of genistein on estrogen receptor mediated pathways.
Carcinogenesis 17:271–275.
Warri A, Saarinen NM, Makela S, Hilakivi-Clarke L. 2008. The
role of early life genistein exposures in modifying breast
cancer risk. Br J Cancer 98:1485–1493.
Wei H, Bowen R, Cai Q, Barnes S, Wang Y. 1995. Antioxidant
and antipromotional effects of the soybean isoflavone
genistein. Proc Soc Exp Biol Med 208:124–130.
Weinbauer GF, Niehoff M, Niehaus M, Srivastav S, Fuchs A,
van Esch E, Cline JM. 2008. Physiology and endocrinology
of the ovarian cycle in macaques. Toxicol Pathol 36:7S–23S.
Westwood FR. 2008. The female rat reproductive cycle: a
practical histological guide to staging. Toxicol Pathol
Wietrzyk J, Grynkiewicz G, Opolski A. 2005. Phytoestrogens
in cancer prevention and therapy—mechanisms of their
biological activity. Anticancer Res 25:2357–2366.
Witte JS, Ursin G, Siemiatycki J, Thompson WD, PaganiniHill A, Haile RW. 1997. Diet and premenopausal bilateral
breast cancer: a case–control study. Breast Cancer Res
Treat 42:243–251.
Wood CE, Messina MJ. 2008. Soy isoflavones, estrogen
therapy, and breast cancer risk: analysis and commentary.
Nutr J 7:17.
Wood CE, Barnes S, Cline JM. 2002. Phytoestrogens and health:
cancer: effects on the breast and uterus. In: Gilani GS,
Anderson JJB, editors. Phytoestrogens and health. Champaign, IL: American Oil Chemist’s Society Press. p 440–469.
Wood CE, Register TC, Anthony MS, Kock ND, Cline JM.
2004. Breast and uterine effects of soy isoflavones and
conjugated equine estrogens in postmenopausal female
monkeys. J Clin Endocrinol Metab 89:3462–3468.
Wood CE, Usborne AL, Starost MF, Tarara RP, Hill LR,
Wilkinson LM, Geisinger KR, Feiste EA, Cline JM. 2006a.
Hyperplastic and neoplastic lesions of the mammary gland
in macaques. Vet Pathol 43:471–483.
Wood CE, Register TC, Franke AA, Anthony MS,
Cline JM. 2006b. Dietary soy isoflavones inhibit estrogen
effects in the postmenopausal breast. Cancer Res 66:
Wood CE, Appt SE, Clarkson TB, Franke AA, Lees CJ,
Doerge DR, Cline JM. 2006c. Effects of high-dose soy
isoflavones and equol on reproductive tissues in female
cynomolgus monkeys. Biol Reprod 75:477–486.
Wood CE, Clarkson TB, Appt SE, Franke AA, Boue SM,
Burow ME, McCoy T, Cline JM. 2006d. Effects of soybean
glyceollins and estradiol in postmenopausal female monkeys. Nutr Cancer 56:74–81.
Wood CE, Register TC, Cline JM. 2007. Soy isoflavonoid effects
on endogenous estrogen metabolism in postmenopausal
female monkeys. Carcinogenesis 4:801–808.
Wu AH, Ziegler RG, Horn-Ross PL, Nomura AM, West DW,
Kolonel LN, Rosenthal JF, Hoover RN, Pike MC. 1996. Tofu
and risk of breast cancer in Asian-Americans. Cancer
Epidemiol Biomarkers Prev 5:901–906.
Wu AH, Ziegler RG, Nomura AM, West DW, Kolonel LN,
Horn-Ross PL, Hoover RN, Pike MC. 1998. Soy intake and
risk of breast cancer in Asians and Asian Americans. Am J
Clin Nutr 68:1437S–1443S.
Wu AH, Stanczyk FZ, Hendrich S, Murphy PA, Zhang C,
Wan P, Pike MC. 2000. Effects of soy foods on ovarian
function in premenopausal women. Br J Cancer 82:
Wu AH, Stanczyk FZ, Seow A, Lee HP, Yu MC. 2002a. Soy
intake and other lifestyle determinants of serum estrogen
levels among postmenopausal Chinese women in Singapore.
Cancer Epidemiol Biomarkers Prev 11:844–851.
Wu AH, Wan P, Hankin J, Tseng CC, Yu MC, Pike MC. 2002b.
Adolescent and adult soy intake and risk of breast cancer in
Asian-Americans. Carcinogenesis 23:1491–1496.
Xu X, Duncan AM, Wangen KE, Kurzer MS. 2000. Soy
consumption alters endogenous estrogen metabolism in
postmenopausal women. Cancer Epidemiol Biomarkers
Prev 9:781–786.
Yuan JM, Wang QS, Ross RK, Henderson BE, Yu MC. 1995.
Diet and breast cancer in Shanghai and Tianjin, China. Br J
Cancer 71:1353–1358.
Zheng W, Dai Q, Custer LJ, Shu XO, Wen WQ, Jin F,
Franke AA. 1999. Urinary excretion of isoflavonoids and the
risk of breast cancer. Cancer Epidemiol Biomarkers Prev
Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AM,
West DW, Wu-Williams AH, Kolonel LN, Horn-Ross PL,
Rosenthal JF, Hyer MB. 1993. Migration patterns and
breast cancer risk in Asian-American women. J Natl Cancer
Inst 85:1819–1827.
Am. J. Primatol.
Без категории
Размер файла
181 Кб
interactions, cynomolgus, fascicularis, macaque, estrogenisoflavone, macaca
Пожаловаться на содержимое документа