Occurrence of Hormonally Active Compounds in Food A Review

Eur Food Res Technol (1999) 209 : 153179
Q Springer-Verlag 1999
REVIEW
Sonja Fritsche 7 Hans Steinhart
Occurrence of hormonally active compounds in food: a review
Received: 12 August 1998 / Revised version: 3 November 1998
Abstract The present review gives an overview of the

occurrence of hormones, hormone mimics, and hormone antagonists in food. The first part deals comprehensively with concentrations of the human sex steroid
hormones progesterone, 17b-estradiol estrone, and testosterone in animal and vegetable food. The dietary intake of steroid hormones (10 mg/day progesterone,
0.1 mg/day estrogens, and 0.05 mg/day testosterone) is
negligible compared to the human endogenous hormone synthesis. The second part addresses the phytoestrogens (isoflavones, coumestans, other bioflavonoids,
lignans, phytosterols), which occur in food in much
higher amounts than steroid hormones. Therefore, they
can cause hormonal effects although their estrogen
equivalents (relative to 17b-estradiol) are estimated to
be 10 210 4. These effects can be beneficial or adverse,
depending on the effectiveness and amount of the ingested hormone agonist, synergistic, and antagonistic
effects with other dietary or endogenous hormones, interactions with other dietary compounds (e.g. fiber and
fat intake), and the hormonal status of the individual.
The review also summarizes the occurrence of steroid
hormone precursors and of other growth-related hormones in food (corticosteroids, indole-3-carbinol, protein hormones). It ends with the presentation of residues and contaminants of fungal or anthropogenic origin (mycoestrogens, pesticides, plastic or food additives, industrial chemicals) which have also shown hormonal or hormone-blocking properties.
S. Fritsche 1 7 H. Steinhart (Y)

Institut fr Biochemie und Lebensmittelchemie,
Universitt Hamburg, Grindelallee 117, D-20146 Hamburg,
Germany
Present address:
1
Growth Biology Laboratory, Livestock and Poultry Sciences
Institute, Agricultural Research Service,
U. S. Department of Agriculture, Beltsville, MD 20705-2350, USA
Key words Hormones 7 Food 7 Steroids 7

Phytoestrogens
Introduction
Incidences of hormonally dependent diseases (e.g. testicular cancer, breast cancer) are increasing in Western
countries [1]. Furthermore, a decrease in human sperm
count and quality has been claimed [2]. In animals in
the wild which were exposed to high doses of environmental pollutants, disturbances of fertility and malformations could be observed [3]. Similar effects could be
detected in livestock animals which were fed with particular fodder plants [4].
Besides these negative effects, a number of positive
effects related to exposure to hormonally active compounds have also been reported. Plant-derived dietary
estrogens have shown preventive effects with regard to
carcinogenesis in animal and cell culture studies [5]. Ingestion of considerable amounts of these phytoestrogens was also linked to the reduced incidence of breast
and prostate cancer in Asian populations [6]. Some authors therefore recommended an increased consumption of phytoestrogen-containing soy products [7].
The sum of these observations increased research on
the human exposure to hormonally active compounds
of natural or anthropogenic origin. A number of reviews have been published summarizing the concentrations of phytoestrogens in vegetable foods [810], but
only limited information is available on the content of
steroid hormones in food [11].
Mammalian sex hormones

The present review will focus mainly on compounds
which act as sex hormones in humans or which interfere with the activity of human sex hormones. In addition, a few other growth-related hormones will be addressed at the end of the review.
154
Fig. 1 Biosynthesis and metabolism of human steroid hormones
Human and mammalian sex hormones a have steroid structure. These compounds are synthesized in
particular glands (ovaries, testes, adrenal glands) from
their basic precursor cholesterol and are secreted into
the circulation. An overview of the biosynthesis of human steroid hormones is given in Fig. 1. Steroid hormones are metabolized to more polar compounds to facilitate elimination. The most frequently occurring
reactions are hydrogenation of the double bonds, hydroxylation, predominantly at C2, C6, and C16, and
conjugation of the oxygenated functional groups, mainly with glucuronic or sulfuric acid.
The effects of steroid hormones become visible after
a time lag of a few hours, which is due to their mode of
action. After having been transported to the target organs and having passed the cell membrane, the steroids
bind to cytoplasmatic receptors. The hormone-receptor
complex binds to a specific promoter sequence on the
deoxyribonucleic acid (DNA) in the nucleus to influence the transcription of messenger ribonucleic acid
(mRNA). The mRNA codes the synthesis of proteins
which may function as enzymes that control metabolic
processes [12].
Sex hormones are organ specific rather than sex specific. They influence not only sex organs but also any
other tissue or organ of the body [13]. In muscle tissue,
for example, androgen, estrogen, and glucocorticoid receptors have been detected [14]. Different effects are
produced by organ-specific patterns of steroid metabolizing enzymes or by interaction with receptors of other
steroid classes. Thus, androgens can be aromatized to
estrogens in peripheral tissues or androgen metabolites
can interact with estrogen receptors.
The activity of steroid hormones is also regulated by
the proportion of free circulating hormones and hormones which are bound to steroid hormone-binding
155
proteins, e.g. albumin or sex hormone-binding globulin

(SHBG).
Estrogens
The expression estrogen generally defines a substance
which stimulates mitotic activity in tissues of the female
genital tract. Numerous compounds ingested with foodstuffs exhibit this effect. Besides natural steroidal estrogens, bioflavonoids and industrial chemicals (e.g. alkylphenols, phthalates, organochlorine compounds)
have also to be considered.
The most important human estrogens are 17b-estradiol and estrone (Fig. 1). 17a-estradiol is less active
than the b-epimer. Estriol is a weak estrogenic metabolite which is predominantly formed and released during pregnancy. Despite their weak estrogenicity,
chronic exposure to 17a-estradiol and estriol may lead
to estrogenic effects [15]. Furthermore, estriol has a low
affinity for SHBG, which can result in an enhanced
bioavailability.
Steroidal estrogens are linked to induction of carcinogenesis. It used to be believed that steroid hormones
only played a role in the promotion of tumors because
of their overall growth promoting properties. It was
therefore concluded that these compounds are not carcinogenic at concentrations below the hormonal effect
level [16]. However, estrogenicity (17b-estradiol 1 estrone 1 1 estriol 1 17a-estradiol) does not directly parallel carcinogenicity [17]. Furthermore, estrogens also induce DNA adduct formation and numerical chromosome aberrations in Syrian hamster embryo (SHE)
cells which express no measurable level of estrogen receptor (ER) [1820]. An additional mechanism may be
the metabolic activation to catechol metabolites. Estrone, which has shown to be strongly carcinogenic in
hamster kidney [21], showed the highest extent of catechol formation, followed by 17b-estradiol (1/5 relative
to estrone) and estriol (1/100) [22]. The catechol metabolites can generate free radicals, which can also lead
to DNA damage [23]. 17a-estradiol does not seem to
be carcinogenic [18, 21]. Estriol has even been said to
have protective properties [24, 25].
Steroidal estrogens are also antioxidants and can exert preventive effects, e.g. with regard to coronary artery atherosclerosis or Alzheimers disease [26, 27].
Androgens and progestins

The main gonadal androgen is testosterone, which is
known for its protein anabolic properties. In some peripheral tissues, testosterone can be converted to 5adihydrotestosterone, which has an even higher affinity
to the androgen receptor (AR). Another source of androgens is the adrenal cortex, which synthesizes considerable amounts of the weak androgens dehydroepiandrosterone (DHEA) and androstenedione. These
adrenal androgens can be converted to testosterone (or

estrogens) in peripheral tissues.
Androgens have been linked to the risk of cardiovascular disease in men. Testosterone is said to have a
lowering effect on high density lipoprotein (HDL) cholesterol levels in males (but not in females), but results
of clinical trials and epidemiological studies are contradictory [28, 29].
Doses of testosterone comparable to those used by
athletes and body builders led to a dramatic decrease of
life span in male mice (owing to tumors or other kinds
of damage to liver, kidney, and heart); levels well below
those used by female athletes and body builders led to
detectable responses in behavior and physiological
characteristics in female mice [30, 31].
Epitestosterone (17a-epimer of testosterone) is said
to act as a weak anti-androgen. Evidence is provided by
the competitive binding to AR, the moderate suppression of gonadotropins and the competitive inhibition of
5a-reductase [32].
The only natural progestin in humans and mammals
is progesterone, which only has a function in females
(preparation for and maintenance of pregnancy). The
exogenous administration of progesterone can reduce
the estrogenic effects of simultaneously administered
estrogens, probably by suppressing the ER concentration [33]. Progesterone is also said to reduce testosterone-induced aggressive behavior by inhibiting the formation of testosterone metabolites [34].
In cell culture studies, androgens and progestins
were able to induce morphological transformation of
SHE cells at 30 mg/ml but were not able to induce gene
mutations or significant increases in frequencies of
chromosome aberrations or aneuploidy [35].
Occurrence of steroid hormones in food

The publics attention has focused on hormone residues
in meat, mainly beef and veal [36]. However, steroid
hormones are also natural constituents of muscle and
fatty tissues as well as of liver and kidney of nontreated animals [37] and even of bones [38] and brain
[39, 40]. Their occurrence is not restricted to mammals.
Steroid hormones have also been determined in fish
[11] and poultry [41, 42]. Furthermore, they have been
found in other animal-derived food such as eggs [11]
and milk [43]. Even plants contain compounds with the
same structure as steroid hormones or their precursors
[44]. In the following, an overview is given of the occurrence of natural steroid hormones in food.
Steroid hormones in beef and veal
Most data are available on the concentrations in beef
and veal. The values are summarized in Tables 1 and 2.
They are in good agreement with each other, although
the data were obtained with different methods [mostly
156
Table 1 Concentrations of steroid hormones in beef (mg/kg); meanBstandard deviation or median (range) a
Progesterone
Bulls
(intact males)
Muscle
0.3 (~0.30.4) [45]

0.17 (0.060.60) [46]
Liver
Kidney
Fat
Steers
(castrated males)
Muscle
Liver
Kidney
Fat
Heifers,
cyclic cows
(females)
Muscle
Liver
Kidney
Fat
Pregnant cow
Muscle
18.9 (5.843.7) [45]

22.7B4.7 cl [51]
3.78B1.00 cf [51]
1.50B0.32 cl [51]
0.79B0.25 cf [51]
3.24B0.70 cl [51]
0.76B0.13 cf [51]
16.7B16.8 [53]
37.9B5.5 cl [51]
17.4B7.3 cf [51]
10.1B6.6 [50]
0.5 (~0.22.8) [45]

0.34 (0.081.05) [46]
0.73B0.10 [47]
0.78B0.73 [48]
1.44B0.86 [49]
0.75B0.41 [48]
2.82B0.17 [47]
5.26B0.66 [47]
10.95B8.68 [48]
~0.2 [45]
0.01 (~0.010.14) [46]
1.05B0.57 [49]
~0.2 [45]
0.07B0.01
0.09B0.03
0.02B0.01
0.19B0.10
0.01B0.00
[47]
[48]
[50]
[48]
[50]
0.61B0.07 [47]
0.03B0.01 [50]
0.25B0.06 [48]
0.01B0.00 [39]
~0.01 [39]
0.04B0.00 [39]
~0.01 [50, 51]
0.01B0.00 [52]
~0.01 [50, 51]

0.00B0.01 [52]
0.01B0.00 [51]
~0.01 [50]
0.01B0.00 [51, 52]
~0.01 [50]
0.01B0.01 [51, 52]
0.02B0.00 [52]
0.01B0.00 [51]
~0.01 [50, 51]
0.01B0.01 [51, 52]
0.05B0.00 [52]
0.01B0.00 [51]
~0.01 [50]
0.01B0.02 [51, 52]
0.01B0.01 [50]
0.01B0.02 [52]
0.00 cl,cf [51]
~0.01 [50]
0.03B0.00 [39]
0.01B0.00 cl,cf [51]
~0.01 [50]
0.04B0.00
0.04B0.00
0.00 [51]
0.01B0.00
0.01B0.01
0.02B0.00
[52]
[52]
[52]
[50]
[51]
0.30B0.16 t1 [50]
0.42B0.18 t3 [50]
0.02B0.01 t1 [50]
0.03B0.02 t3 [50]
3.42B1.37 [50]
0.04B0.01 t1 [50]
0.27B0.07 t3 [50]
0.06B0.05 t1 [50]
1.03B0.37 t3 [50]
Kidney
6.19B1.86 [50]
1.93B0.45 t1 [50]
4.01B2.27 t3 [50]
0.13B0.05 t1 [50]
0.27B0.08 t3 [50]
0.41B0.10 t1 [50]
0.69B0.23 t3 [50]
0.03B0.01 t1 [50]
0.07B0.03 t3 [50]
0.02B0.01 t1 [39]
0.06B0.01 t3 [39]
~0.01 t1 [54]
0.100.13 t3 [54]
239B116 [50]
336B107 [53]
Estrone
0.01B0.00 [39]
Liver
Fat
0.4 (~0.31.7) [45]

0.23 (0.012.33) [46]
0.27B0.33 [50]
3.89B0.77 [51]
0.98B0.21 [51]
0.26B0.07 [50]
0.35B0.06 [51]
0.18B0.02 [51]
1.61B0.29 [51]
0.40B0.08 [51]
2.48B1.61 [50]
4.55B0.79 [51]
2.50B0.28 [51]
17b-Estradiol
Testosterone
0.02B0.00 [39, 51]

~0.01 [50]
0.07B0.00 [52]
~0.01 cl,cf [51]
0.04B0.03 [52]
0.01B0.00 cl [50, 51]
0.02B0.00 cf [51]
0.03B0.00 [39]
0.20B0.02 t1 [50]
0.52B0.24 t3 [50]
0.01B0.00 t1 [39]
0.21B0.04 t3 [39]
0.03B0.03 t1 [50]
0.15B0.06 t3 [50]
0.02B0.01 t1 [39]
0.25B0.05 t3 [39]
0.08B0.00 t1 [50]
0.14B0.04 t1 [50]
0.01B0.00 t1 [39]
0.55B0.07 t3 [39]
0.78B0.64 t1 [50]
2.77B1.50 t3 [50]
0.01B0.00 t1 [39]
3.96B0.55 t3 [39]
0.04B0.34 t1 [54]
1.743.00 t3 [54]
c1, cow, luteal stage; cf, cow follicular stage; t1, 1st trimester of pregnancy; t3, 3rd trimester of pregnancy
radioimmunoassay or gas chromatography-mass spectrometry (GC-MS)] and the samples were taken from
different kinds of muscle and adipose tissue. In some
studies, conjugated hormones were included; other researchers determined only free hormones. Furthermore, breed, age, and feeding of the animals as well as
stress and other environmental factors have an influence on hormone content. Nevertheless, the values
cover a narrow physiological range. Highest amounts
were determined in fat, whereas muscle tissues and offal show comparatively low amounts. Concentrations of
the estrogens 17b-estradiol and estrone generally lie
below 0.1 mg/kg. The only exception are tissues of pregnant cattle, which rarely enter the normal slaughter
process. Natural progesterone concentrations range

from 0.01 mg/kg up to 5 mg/kg in edible tissues of male
cattle and from 0.5 mg/kg up to 40 mg/kg in female cattle. Highest concentrations are reached in the fat of
pregnant cattle (up to 400 mg/kg). Highest amounts of
testosterone are reached in the fat of mature bulls
(520 mg/kg), whereas other tissues of bulls contain
0.13 mg/kg. Even lower amounts were determined in
tissues of heifers and steers. Concentrations of epitestosterone, the 17a-epimer of testosterone, reach concentrations of 0.11.0 mg/kg in beef from both bulls and
steers [46]. Calves generally show similar tissue concentrations of steroid hormone as adult cattle (Table 2).
157
Table 2 Concentrations of steroid hormones in veal (mg/kg); meanBstandard deviation or range a
Calves
(male/female)
Progesterone
Testosterone
17b-Estradiol
Estrone
Muscle
0.25B0.09 [55]
0.11B0.14 [56]
0.000.03 [57]
0.08B0.04 [56]
0.020.08 [57]
Liver
0.27B0.11 [55]
0.02B0.01 [48]
0.030.77 m [57]
0.16B0.02 m [47]
0.010.42 f [57]
0.08B0.01 f [47]
0.04B0.02 [48]
0.100.32 m [57]
0.010.12 f [57]
0.5810.17 m [57]
1.82B0.15 m [47]
0.060.38 f [57]
0.57B0.05 f [47]
0.18B0.12 [48]
0.273.88 m [57]
3.57B0.64 m [47]
0.020.17 f [57]
0.49B0.03 f [47]
0.07B0.16 [56]
0.000.05 [57]
0.20B0.09 [56]
0.170.20 [57]
0.010.07 [57]
0.020.17 [57]
0.13B0.06 [56]
0.000.05 [57]
0.28B0.08 [56]
0.080.09 [57]
Kidney
Fat
5.8B2.5 [53]
f, female; m, male
Anabolic steroids as performance enhancers

in cattle fattening
Because of their growth promoting properties, sex steroids are administered as performance enhancers to
cattle with low endogenous hormone synthesis rates,
e.g. veal calves and steers. This practice is not allowed
in the European Union (EU). However, it is assumed
that about 10% of all meat consumed in the EU contains added hormones [58]. A limited number of natural steroid hormones (testosterone, progesterone, 17bestradiol) and synthetic hormonally active compounds
(zeranol, trenbolone) have been approved in several
countries, such as the USA, Australia, or Canada.
These anabolic compounds are implanted in non-edible
parts of the animals, where they deliver the hormones
at a consistent rate. Most scientists consider the controlled administration of these compounds as safe, as
well as the Codex Alimentarius Commission, a joint
UN Food and Agricultural Organization (FAO)/World
Health Oganization (WHO) body responsible for international food standards. Therefore, the World Trade
Organization (WTO) has declared that the EU ban on
meat imports with hormones infringes the free trade
principle amongst WTO parties. However, European
consumers are considerably concerned about residues
of hormones in meat [59], which is probably due to a
number of scandals where the misuse of anabolic hormones in cattle fattening was exposed [60]. The compound which provoked the most disapproval was diethylstilbestrol (DES). It was banned as a performance
enhancer in most countries in the 1970s because the
clinical use of this compound in women (to prevent
abortion) led to particular kinds of vaginal cancer in
some of their daughters. In 1980, high concentrations of
DES were detected in European baby food [61]. One of
the consequences was the total ban of hormones as
growth promoters in the EU. The content of steroid
hormones in meat from treated cattle are well within

the physiological range of untreated cattle (Table 3).
Similar results have been reported for sheep tissues
(liver, kidney, muscle, fatty tissue) after implantation of
progesterone [62]. However, it should not be disregarded that metabolites of the administered hormones
could be accumulated. Thus, levels of free 17a-estradiol
in the liver and kidney of steers that had been treated
with 17b-estradiol exceeded the values of control steers
five-fold (0.05 vs 0.01 mg/kg) [39]. Similar observations
were made with regard to levels of total 17a-estradiol
in the liver of treated and control veal calves [57].
Residues of hormonally active compounds in edible
tissues of cattle or sheep which had been treated with
the synthetic anabolic steroid trenbolone acetate
(TBA) and slaughtered after the recommended withholding period amounted to 0.050.13 mg/kg in muscle
and to 0.230.6 mg/kg in offal [53, 63, 64]. The non-steroidal anabolic compound zeranol might lead to higher
residue concentrations because of its long half-life [16].
It can be conluded that consumers are not exposed
to higher amounts of steroid hormones if they eat meat
from cattle treated according to good husbandry practice. However, if a treatment is carried out improperly
(e.g. injection in edible tissues or use of non-approved
compounds), intoxications cannot be excluded. Outbreaks of food poisoning due to illegal treatment with
the orally potent b-agonist clenbuterol (which increases
muscle and decreases fat accretion in cattle, sheep, pigs
and poultry) have been reported [65, 66].
Steroid hormones in milk and milk products
It is known that steroid hormones pass the blood-milk
barrier. This effect has been used for diagnosis of pregnancy in cattle by analysing the progesterone content in
milk [67]. The mechanism of transport (active or pas-
158
Table 3 Concentration of steroid hormones in beef from treated cattle (mg/kg); meanBstandard deviation or range a
Progesterone
Steers
Muscle
1.93B0.27 a [51]
1.70B0.20 b [51]
Liver
0.45B0.07 a [51]
0.40B0.04 b [51]
Kidney
1.08B0.13
0.23B0.05
2.96B0.60
2.62B0.27
Fat
Veal calves
(male/female)
Muscle
Liver
Kidney
Fat
12.5 [53]
Testosterone
a [51]
b [51]
a [51]
b [51]
0.040.42
0.060.31
0.07 [48]
0.020.10
~0.010.32
0.05 [48]
0.170.31
0.200.87
0.69 [48]
0.292.98
0.261.74
0.34 [48]
17b-Estradiol
Estrone
~0.01 a [51]
0.01B0.00 b [51]
0.02 [39]
0.01B0.00 a [51]
~0.01 b [51]
0.08 [39]
0.01B0.00 a [51]
0.01B0.00 b [51]
0.01B0.00 a [51]
0.01B0.00 b [51]
0.05 [39]
~0.01 a [51]
~0.01 b [51]
0.01 [39]
0.01B0.00 a [51]
0.01B0.00 b [51]
0.06 [39]
~0.01 a [51]
0.01B0.00 b [51]
0.01B0.00 a [51]
0.01B0.00 b [51]
0.06 [39]
m [57]
f [57]
0.010.28 [57]
~0.010.07 [57]
m [57]
f [57]
0.011.65 [57]
0.070.28 [57]
m [57]
f [57]
0.010.59 [57]
0.030.14 [57]
m [57]
f [57]
0.010.34 [57]
0.030.15 [57]
a
f, female; m, male; [53], slaughtered 70 days after implantation
of 20 mg 17b-estradiolc200 mg progesterone; [48], slaughtered
77 days after implantation of 20 mg 17b-estradiolc200 mg testosterone; [39], slaughtered 3 months after implantation of 17bestradiol impregnated rubber; [57], slaughtered 1570 days after
implantation of 20 mg 17b-estradiolc200 mg progesterone or testosterone orc140 mg trenbolone; [51], slaughtered (a) 30 days or
(b) 60 days after implantation of 20 mg 17b-estradiolc200 mg
progesterone
sive) is discussed in the literature as well as the synthesizing and metabolizing potential of the mammary
gland [68, 69]. As expected, most information is available about the progesterone content in milk and milk
products (Table 4). Concentrations range from 1.4 mg/l
in skim milk to about 10 mg/l in whole milk and to
about 300 mg/kg in butter, depending on the fat content. A strong correlation of the levels of lipophilic hormones (e.g. progesterone and estrone) with the milk fat
content, which is due to the hormones fat solubility,
has been proved [11]. As this fat solubility is temperature dependent, the temperature of whole milk prior to
centrifugation has a significant influence on the progesterone content of the resulting cream and skim milk
[75].
Progesterone, estradiol, and estrone are located in
the core fat rather than in the fat globule membrane
[76]. In distribution studies with [ 3H]progesterone, milk
fat contained 80% of the labeled progestogen, casein
made up 19% (also indicating some protein binding),
and whey made up 1% [77]. The protein binding property of progesterone can also be observed in proteinconcentrated milk products like dried milk (Table 4).
Milk products can in general be considered as a rich
source of steroids. The hormone pattern resembles that
of meat from female cattle. The main estrogen in milk
is the biologically less active 17a-estradiol (about
0.16 mg/l), followed by estrone and 17b-estradiol [68].
Food processing, such as heating or churning, appears to have no effect on the hormone patterns, al-
though cheese ripening does. In milk and also in noncheese milk products with a higher fat content, only
small amounts of testosterone could be determined
(~0.010.15 mg/l). In different kinds of cheese, however, testosterone occurred in concentrations ranging
from 0.07 mg/kg up to 1.41 mg/kg. Probably fermenting
bacteria or clotting enzymes are responsible for the formation of testosterone during the cheese manufacturing and ripening. The metabolic intermediate androstenedione or even the androgen metabolite estrone,
which are both present in milk [11, 69], may possibly be
precursors for testosterone.
Steroid hormones in pork and meat products
The concentrations of hormonally active steroids in
pork are similar to those in beef (Table 5). Between
gilts (female pigs) and barrows (castrated males), no
marked differences were found. Tissues of boars (intact
males) show comparatively high concentrations of both
estrogens and androgens [78]. The high synthesis of steroid hormones explains the superiority of boars compared to gilts and barrows in fattening traits and carcass
composition [80]. Boar fattening is approved by the EU
but meat from boars is not routinely marketed in Germany. The reason is the high incidence of the urine-like
boar odor caused by the steroid 5a-androstenone,
which is highly correlated to androgen and estrogen
synthesis [81].
159
Table 4 Concentrations of steroid hormones in milk (mg/l) and milk products (mg/kg), meanBstandard deviation or range a
Fat (%)
Skim milk
0.1
Fat reduced milk
1.5
Whole milk
3.5
Cream
32
Butter
82
Buttermilk
1.0
Sour milk
(fat reduced)
Yoghurt
1.5
Condensed milk
Dried milk (skim)
Dried milk (whole)
Ricotta
Cheese (fresh)
Cheese (fresh)
Cheese (half ripened)
Cheese (ripened)
Cheese (Gouda)
Cheese
(propionic ferment.)
a
Progesterone
2.1B0.6 [70]
1.4 [71]
4.6B0.4 u [70]
5.8B0.4 [70]
6.0 [71]
9.81 [11]
9.5B0.5 [70]
11.812.5 [71]
11.3B0.06 u [70]
41.848.6 [11]
72.7B5.8 [70]
43.0 u [71]
58.7B5.3 8 [70]
132.9B5.1 [70]
300.0 [71]
141 [11]
3.0
13.3 [11]
12.3 [71]
17.1 [71]
98.4 [71]
29
17b-Estradiol
Estrone
~0.01 [11]
0.020.12 u [69]
0.050.15 u [48]
~0.03 [11]
~0.02 [11]
0.03B0.00 u [68]
0.010.06 u [72]
0.04B0.01 c [73]
0.09B0.01 t1 [73]
0.05B0.02 t3 [73]
~0.03 [11]
0.13 [11]
0.01B0.00 u [68]
0.030.12 u [72]
0.04B0.00 c [73]
0.06B0.02 t1 [73]
0.10B0.02 t3 [73]
0.26 [11]
~0.05 [11]
~0.03 [11]
1.47 [11]
~0.01 [11]
~0.02 [11]
0.16 [11]
4.7B0.8 [70]
6.5 [71]
4.2 [71]
10
1.5
25
11
Testosterone
1.72.0 [74]
3.04.0 [74]
21.530.3 [11]
2.03.5 [74]
~1.03.3 [74]
44.2 [11]
5.910.5 [74]
~0.1 [74]
~0.1 [74]
0.130.15 [11]
~0.1 [74]
~0.1 [74]
0.48 [11]
0.071.41 [74]
0.01 [74]
0.01 [74]
0.020.03 [74]
0.010.03 [74]
~0.03 [11]
~0.010.03 [74]
0.17 [11]
u, unprocessed; c, from cyclic cow; t1, from pregnant cow, 1st trimester; t3, from pregnant cow, 3rd trimester
Liver and fat of barrows and gilts show equivalent

hormone contents to those in muscle tissues (chops), in
contrast to cattle and boars where these hormones are
accumulated in fat. Progesterone has been shown to be
stored in adipose tissues of gilts for only two days [82].
Cooked ham and salami (80% pork) show similar hormone patterns (Table 5) as pig tissues, whereas Frankfurter sausages that contain predominantly beef show a
female-cattle-like profile with high progestogen concentrations. Food processing steps, such as cooking,
smoking and fermenting, appear to have little effect on
the steroid patterns. However, all investigated meat
products had higher testosterone concentrations than
the common ingredients (meat and fat from gilts, barrows and female cattle). This may indicate the partial
use of boar meat for meat products although estrogens,
which in that case would be expected, could not be detected. Another explanation for the occurrence of testosterone in sausages might be a conversion of DHEA
and androstenedione to testosterone during manufacture, as these testosterone precursors were not detectable in salami and Frankfurters.
Steroid hormones in poultry and eggs

Hormones have been routinely used in some countries
to fatten male broiler chickens since the 1930s [83, 84].
However, reports on the content of steroid hormones
in poultry tissues are rare. Abdalla et al. [84] found
physiological 17b-estradiol levels in chicken carcasses
of 20 mg/kg in muscle and 30 mg/kg in fat with thin layer
chromatography (TLC). These values could not be confirmed using GC-MS [11] or radioimmunoassay [41, 42]
(Table 6). Values for muscle tissue and liver did not exceed 0.02 mg/kg except for goose-fat (up to 0.73 mg/kg).
With regard to estrone, only information about plasma
content is available (0.1 ng/ml [85]).
Birds seem, like cattle, to accumulate more lipophilic hormones in fatty tissues with increasing age
(goose-fat, meat of laying hens with approx. 20% fat).
Progesterone concentrations in the plasma of hens
range from 0.5 ng/ml to 20 ng/ml dependent on age and
cycle [86, 87]. These values are reflected in the tissue
concentrations of 0.2 mg/kg in chicken to 7.8 mg/kg in
the laying hen. Natural concentrations of androgens are
very low in poultry: up to 0.03 mg/kg testosterone in
160
Table 5 Concentrations of steroid hormones in pork and meat products (mg/kg); median and/or range
Progesterone
Boars [78]
Muscle
Liver
Kidney
Backfat
Barrows
Muscle
Liver
Kidney
Backfat
0.350.76 [11]
Gilts/
femele pigs
Muscle
1.101.76 [11]
~0.010.03 [79] a
Not specified
Liver
Kidney
Backfat
~0.010.01 [79]
Abdom. fat
~0.010.01 [79]
Liver
Bacon
Ham
Frankfurter
Salami
1.85 [11]
0.71 [11]
0.961.51 [11]
6.82 [11]
0.79 [11]
17b-Estradiol
Testosterone
Estrone
3.71
1.20
13.48
11.96
(0.188.40)
(0.252.42)
(4.7822.1)
(1.2620.34)
0.91
9.67
10.56
0.43
(0.162.45)
(0.3116.90)
(0.0024.36)
(0.120.78)
0.15
3.33
26.06
0.59
(0.020.33)
(0.606.59)
(2.3955.2)
(0.091.38)
0.04
0.04
0.25
0.10
(0.000.16)
(0.000.10)
(0.130.37)
(0.000.22)
0.03
0.08
0.17
0.03
(0.000.07)
(0.020.17)
(0.020.73)
(0.000.06)
[78]
[78]
[78]
[78]
0.08
0.15
0.09
0.03
(0.010.16)
(0.040.28)
(0.010.40)
(0.000.10)
0.06 (0.000.20)
~0.010.01 [79]
0.21 (0.080.32)
0.16 (0.000.91)
0.03 (0.000.12)
~0.010.07 [79]
0.020.07 [79]
[78]
0.03 (0.000.16) [78]
[78]
[78]
[78]
0.32 (0.150.44) [78]

0.31 (0.150.44) [78]
0.05 (0.000.20) [78]
[78]
[78]
[78]
[78]
0.09 (0.000.23) [78]

0.04 (0.000.14) [78]
0.19 (0.100.49) [78]
0.07 (0.000.32) [78]
~0.02 [11]
~0.02 [11]
0.040.05 [11]
0.07 [11]
0.05 [11]
~0.03 [11]
~0.03 [11]
~0.03 [11]
~0.02 [11]
~0.02 [11]
~0.03 [11]
~0.02 [11]
[78]
[78]
[78]
[78]
[79], quartile (2575%)
male broilers and up to 0.02 mg/kg in turkey toms.

However, the German monitoring of turkey revealed
0.20.3 mg/kg testosterone in five of six samples [88]. It
would have to be confirmed if these concentrations
were within the physiological range.
Eggs contain comparatively high amounts of the female steroids (Table 6). This could be expected, as eggs
are produced directly in the hens ovaries. Besides, eggs
are known for their high content of cholesterol, which
is the precursor of steroid hormones. The estrogen metabolites estriol and 17a-estradiol as well as the androgen testosterone were also determined in amounts up to
0.25 mg/kg and 0.5 mg/kg, respectively [11]. Eggs are,
therefore, a considerable source of hormonally active
steroids.
Steroid hormones in fish

Steroid genesis in fish follows a pathway differing from
that in mammals, and the steroids show partly different
functions. In addition to the classical mammalian ste-
Table 6 Concentrations of
steroid hormones in poultry
and eggs (mg/kg); range
Progesterone
Chicken
Chicken liver
Turkey
Laying hen
Goose-fat a
Goose-fat b
Egg
a
b
0.24 [11]
8.18 [11]
7.78 [11]
31.85 [11]
3.83 [11]
12.543.6 [11]
roid hormones, fish-specific hormones such as 11b-hydroxyandrostenedione, 11-ketoandrostenedione, and

11-ketotestosterone have also been detected in plasma
of trout, salmon, plaice, and tilapia [8991]. In some
fish, 11-ketotestosterone is the main androgen, e.g. in
the flounder [90]. Testosterone, on the other hand, can
reach higher concentrations in females than in males
[92, 93].
Progesterone has no progestogenic activity in fish as
it is solely a biosynthetic intermediate. Therefore, no
differences between male and female fish can be detected [92]. The plasma contents of steroid hormones in
fish vary widely, depending on the season and reproductive stage. Basal concentrations are about 0.53 ng/ml;
peak concentrations reach 100 ng/ml and more (at
spawning time) [9498]. The order of magnitude of steroid hormones in fish tissue reflects the basal concentrations determined in fish plasma. In carp and herring,
natural tissue concentrations of ~0.10.51 mg/kg progesterone and ~0.020.07 mg/kg testosterone have
been determined. Estrogens were not detectable
(~0.03 mg/kg 17b-estradiol and ~0.02 mg/kg estrone)
[11].
Testosterone
17b-Estradiol
Estrone
~0.0040.030 [42]
~0.0040.020 [41]
~0.004 [41]
~0.0040.004 [42]
~0.0040.015 [41]
0.73 [11]
0.03 [11]
~0.030.22 [11]
~0.02 [11]
~0.0040.023 [42]
~0.02 [11]
~0.02 [11]
0.06 [11]
0.040.49 [11]
Melted from goose

Commercial (10% pork fat declared, probably gander fat)
~0.02 [11]
0.16 [11]
0.51 [11]
~0.02 [11]
0.180.89 [11]
161
Steroid hormones in plants

The natural occurrence of steroid hormones in plants
and their function have been controversial for more
than 50 years [99]. Steroid hormone precursors and
progesterone, which can also be considered a precursor
for androgens and estrogens, have unequivocally been
isolated from higher plants [11, 44, 100]. The occurrence of steroidal estrogens has been proposed by several authors, e.g. in Graminae (wheat, rice, oats), Leguminosae (beans), and Palmae [8, 101]. The occurrence
of androgens has been reported in pine pollen in
amounts 1 50 mg/kg [102]. These results, however, were
frequently obtained with unspecific techniques (e.g.
bioassays, TLC) after insufficient purification of the
plant extracts. Several attempts to confirm the occurrence of animal hormones in plants with GC-MS or radioimmunoassay failed [103]. For example, Amin and
Bassiouny [104] detected 90 mg/l estrone ester in olive
oil and 40 mg/l estrone in corn oil (confirmation with
TLC, UV, NMR, and IR spectroscopies), but not in sesame, coconut, lettuce, linseed, palm, arachis, cottonseed, or soybean oil. Up to now, only the presence of
estrone in olive oil (only 0.02 mg/kg) [11] and of 17bestradiol and estrone (210 mg/kg) in French beans
(Phaseolus vulgaris) [105, 106] has been supported by
GC-MS analyses. However, the latter could not be confirmed by other research groups [11, 103]. In Table 7,
only current data obtained by GC-MS are presented. In
mushrooms and yeast, no steroid hormones could be
detected, nor could any precursors [11]. In alcoholic
beverages, no steroid hormones but rather the metabolic intermediates DHEA (0.02 mg/kg and 0.10 mg/kg)
and androstenedione (0.02 mg/kg and 0.05 mg/kg) could
be determined in small amounts, which probably originate from the vegetable ingredients.
Interestingly, steroidal hormones have an influence
on the growth, sex expression, and development of
plants [101]. Furthermore, it is known that exogenous
animal steroids can be metabolized by many plants.
This indicates that the required enzyme systems are
present or easily induced in plants [107]. Plants also
synthezise a variety of plant-specific steroids, for example cardenolides, digitanoles, or alkaloids (Fig. 2).
steroid hormones in vegetable
food (mg/kg) according to [11]
Potatoes
Wheat
Rice
Soybeans
Haricot beans (dry)
Mushrooms
Yeast
Olive oil
Corn oil
Safflower oil
Beer
Wine
a
Their biosynthesis may start from the same precursors

as needed for the synthesis of human sex hormones,
namely from cholesterol or pregnenolone, and proceed
partly via the same steps as in animals [108]. Plant-specific steroids may, on the other, hand function as precursors for the animal steroids [44].
Steroid hormones in drinking water

It has been assumed that drinking water could be contaminated by long-acting steroid hormones originating
from pharmaceuticals (e.g. contraceptives). Although
the entry of these compounds has been calculated to
account for only 2% of the total human excretion of
steroid hormones, the pharmacologically active steroids
are persistent compared to the endogenous hormones
[109]. Concentrations of the most prominent compound, 17a-ethinylestradiol, have been determined to
be ~1 ng/l and ~0.01 mg/l in surface water and
~0.1 ng/l and ^0.001 mg/l in drinking [109, 110]. Androgens and progestogens could not be detected in water [110].
Dietary intake of steroid hormones

The dietary intake of steroid hormones in Germany has
been estimated by Hartmann et al.[11]. The estimation,
which was based on data of the German Consumption
Study [111] and a market basket survey [11], revealed a
daily intake of approximately 10 mg progesterone,
0.1 mg estrogens (17b-estradiolcestrone), and 0.05 mg
testosterone. The human daily production exceeds
these values by some orders of magnitude
(0.1520!10 3 mg/day progesterone, 0.050.60!10 3 mg/
day estrogens, 0.036.50!10 3 mg/day testosterone [50]).
Furthermore, natural steroid hormones show only low
oral activity. More than 90% of the ingested hormones
are inactivated by the first-pass mechanism of the liver.
It can be concluded that hormonal effects cannot be expected from the ingestion of naturally occurring dietary
steroid hormones.
Progesterone
Testosterone
17b-Estradiol
Estrone
5.07
0.602.86
0.38
~0.3
~0.3
~0.1
~0.1
0.08
0.31
0.71
~0.05
~0.05
~0.02
0.090.19
?a
~0.05
~0.05
~0.02
~0.02
~0.02
0.05
0.21
~0.01
~0.01
~0.03
~0.07
~0.07
~0.07
~0.07
~0.03
~0.03
~0.03
~0.03
~0.03
~0.01
~0.01
~0.02
~0.05
~0.05
~0.05
~0.05
~0.02
~0.02
0.02
~0.02
~0.02
~0.01
~0.01
?, not interpretable owing to interferences
162
Fig. 2 Biosynthesis of plant
specific steroids
Occurrence of steroid hormone precursors in food

As already indicated in the preceding section, foodstuffs not only contain the hormones themselves but
also their natural precursors and metabolites (e.g. androsterone, dihydrotestosterone, hydroxyprogesterone)
[11]. It cannot be excluded that precursors might be
converted into actual hormones during fermentation or
ripening processes or in the human intestinal tract. Be-
sides, numerous human peripheral tissues (e.g. skin, fat,

prostate, breast) possess the enzymatic machinery to
convert steroid precursors into potent androgens and
estrogens. It might therefore be advisable to examine
the occurrence of hormone precursors in food. The
concentrations of the main precursors pregnenolone,
DHEA, and androstenedione in beef are given in Table 8. A summary of the occurrence of these precursors
in other foodstuffs is presented in Table 9.
163
Table 8 Concentrations of steroid hormone precursors in beef (mg/kg); meanBstandard deviation or median (range)
Pregnenolone
Bulls
(intact males)
Muscle
Androstenedione a
DHEA
0.67 (0.352.37) [46]

1.7 (0.85.0) [45]
2.4 [11]
0.24 (0.081.51) [46]

0.3 (0.20.5) [45]
0.9 [11]
0.39 (0.040.78) [46]

0.6 (~0.21.2) [45]
0.8 [11]
0.37B0.05 [47]
1.28B0.23 [47]
10.31~0.88 [47]
Kidney
Fat
Steers
(castrated males)
Muscle
1.24 (0.313.07) [46]

1.7 (0.55.9) [45]
1.4 [11]
0.19 (0.080.53) [46]

~0.2 (~0.20.7) [45]
0.1 [11]
0.24 (0.050.92) [46]

~0.2 (~0.22.5) [45]
0.2 [11]
Heifers/cows
(females)
Muscle
2.8 (1.06.5) [45]

1.1 [11]
~0.2 (~0.20.6) [45]

0.5 [11]
0.3 (~0.24.3) [45]

0.4 [11]
0.13B0.01 [47]
1.07B0.13 [47]
2.56B0.42 [47]
Fat
Calves
(male/female)
Muscle
0.44B0.04
0.22B0.04
0.78B0.18
0.53B0.05
17.45B2.77
2.32B0.60
Fat
a
m [47]
f [47]
m [47]
f [47]
m [47]
f [47]
m, male; f, female
steroid hormone precursors in
food (mg/kg) according to [11]
(single values or range)
Pregnenolone
Milk
Cream
Butter
Yoghurt
Fresh cheese
Gouda cheese
Pork
Liver
Bacon
Ham
Frankfurter
Salami
Chicken
Turkey
Laying hen
Goose fat a
Goose fat b
Egg
Herring
Carp
Potatoes
Wheat
Rice
Soybeans
Haricot beans (dry)
Mushrooms
Yeast
Olive oil
Corn oil
Safflower oil
Beer
Wine
a
DHEA
2.09
7.812.2
49.6
3.01
5.115.48
12.0
0.13
0.140.31
1.15
0.11
0.180.26
0.17
0.100.37
1.78
0.41
0.340.64
1.16
0.20
0.010.14
0.22
~0.02
0.240.64
~0.02
~0.02
0.110.19
0.12
0.65
0.090.39
~0.02
~0.02
~0.02
0.05
0.62
1.01
0.30
0.051.76
~0.02
0.06
0.62
0.63
0.09
1.839.27
1.00
0.281.41
0.60
0.160.18
0.29
0.030.06
1.30
0.962.50
2.35
1.29
5.58
~0.01
~0.01
0.45
3.39
1.17
~0.05
~0.05
3.09
0.150.67
0.35
0.31
0.51
~0.02
~0.02
0.04
0.32
~0.02
0.10
0.02
0.05
0.100.48
?c
~0.05
~0.05
~0.02
~0.02
~0.02
?
~0.02
0.05
0.02
0.59
0.25
1.06
8.96
1.66
83.3143
Melted from goose

Commercial (10% pork fat declared, probably gander fat)
c
?, not interpretable owing to interferences
b
Androstenedione
0.13.5 [11, 69]
1.252.10
5.98
0.56
0.941.82
0.77
164
Pregnenolone is the basic precursor for all kinds of

steroid hormones (see Fig. 1). Androstenedione is a D 4intermediate. It is weakly androgenic itself and the direct precursor of the androgen testosterone and the estrogen estrone. The most famous precursor at the moment is DHEA, however. This D 5-intermediate (3b-hydroxy-5-androsten-17-one) is a major steroid secreted
by the adrenal gland. In humans, DHEA reaches highest levels at approximately 25 years of age and declines
dramatically afterwards, with only 10% DHEA remaining at the age of 70 or 80 [112].
DHEA is said to have beneficial effects in countering a wide variety of conditions including cancer [113],
brain aging [114], obesity [115, 116], diabetes, and cardiovascular disease [117]. It has also been shown to
protect mice from a variety of viral, bacterial, or parasite infections, probably through its metabolites [118].
Lower blood levels of DHEA and its sulfate are associated with the development of breast cancer or death
from cardiovascular disease [119121]. In animal studies, oral administration of DHEA has shown chemopreventive properties towards spontaneous, radiation,
and chemically induced mammary cancers [122125].
Dietary DHEA was also able to suppress chemical carcinogenesis in skin [126], lung [127], liver [128], thyroid
[129], and pancreas [130] of experimental animals. Several possible explanations for the chemopreventive
properties of DHEA are discussed, e.g. change of the
endocrinological environment (decreases of progesterone, prolactin, free cholesterol, and triglyceride, increase of serum estradiol) [125], induction of thymic
atrophy and suppression of T cell lymphocytes [131], or
antioxidant activity [132].
In age-advanced men with low endogenous serum
DHEA levels, daily administration of 50 mg DHEA for
20 weeks significantly activated their immune function
[133]. In patients with human immunodeficiency virus
(HIV)-related illness, a positive relationship between
immune status (absolute CD4 lymphocyte levels) and
DHEA was observed, leading to the hypothesis that
DHEA defiency may worsen immune status [134]. In
vitro studies even revealed a modest inhibition of HIV
type I infection [135].
The dietary intake of DHEA in Germany has been
estimated to be approximately 0.5 mg/day [11]. This
amount is negligible compared to the human daily production as well as compared to the doses that have
shown beneficial properties in animal studies (0.3% of
the diet [131]) and clinical studies (50 mg/day [133]).
In the USA, DHEA is already available as an overthe-counter product. The long-term use of DHEA
should be carefully evaluated, however. Some authors
have reported adverse effects of DHEA, e.g. increase
of lipid peroxidation in rats [136, 137] or induction of
lysis of human red blood cells when added in amounts
exceeding the natural plasma levels by three orders of
magnitude [138]. The anticarcinogenic potency of
DHEA has also to be evaluated with caution because it
seems to be dependent on the hormonal status of the
individual. In environments with low or no estrogen,

DHEA can stimulate tumor growth [139, 140]. For example, in rats and rainbow trout, DHEA has been
shown to be hepatocarcinogenic, which might be due to
peroxisome proliferation [141] or to its function as a
sex steroid precursor [142]. Orally administered DHEA
is metabolized to androgens and estrogens and elevates
serum levels of these hormones in rainbow trout and
humans [143, 144].
Non-steroid dietary hormone mimics or antagonists

Many foodstuffs and herbs have shown themselves to
be able to induce endocrine effects in humans and animals. Estrogenic effects of particular plants have been
observed in grazing animals [4]. A famous example is
clover-disease, an infertility problem observed in
sheep grazing on clover [145]. Particular plants (e.g.
pomegranate, date) have been historically used as sex
hormones in native medicine [8].
An endocrine effect can be achieved by disruption
of hormone synthesis, secretion, transport, interaction
with receptor molecules, metabolism, or elimination.
Natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind the ER in intact
cells but demonstrate marked differences in their ability to induce end products of estrogen action (e.g. enhancement of DNA synthesis or stimulation of the
transcription of estrogen-responsive genes) and to regulate cell proliferation [146]. All the classes of estrogens mentioned above stimulate cell proliferation at
concentrations that half-saturate the ER [146]. Compounds binding to the progesterone receptor (PR) are
neutral or antagonists rather than agonists [147]. Soy,
licorice, red clover, thyme, tumeric, hops, and verbena
are the plants with the highest observed ER binding,
and oregano, verbena, tumeric, thyme, red clover, and
damiana show the highest PR binding [147]. Other
classes of compounds, such as cannabinoid compounds,
exert potent effects on luteinizing hormone and prolactin release but fail to stimulate ER and transcriptional
activity [148].
Phytoestrogens
Several classes of compounds which can bind to the
mammalian estrogen receptor have been detected in
plants. In vitro studies showed that the affinities of
these phytoestrogens to ER range from 10 2 to 2!10 5
compared to 17b-estradiol. The relative potency to
enhance alkaline phosphatase in human endometrial
adenocarcinoma cells was measured to be 5!10 2 to
~10 5 [149]. The dietary estrogen equivalents are estimated to be 10 210 3 [150].
Effects of phytoestrogen-containing foods
In populations where large amounts of soy products are
consumed, e.g in Asian countries, a lower incidence
165
and mortality from breast cancer compared to the

Western world can be observed. In premenopausal Singapore Chinese women a strong correlation between
the intake of soy protein and a reduction in the risk of
breast cancer has been shown [151]. In a classical animal model (N-methylnitrosourea-induced breast cancer
in rats) the appearance of mammary tumors could be
inhibited by soy intake [152]. The amounts of soy given
in this animal experiment were similar (on a body
weight basis) to those consumed by Asians (approximately 1035 g soybean equivalents per day). Further
epidemiological studies and long-term studies with rodents revealed a protective effect of soy products
against ovary, endometrial, lung, colon, stomach, liver,
bladder, and prostate cancer or other diseases which
are due to hormonal imbalance such as cardiovascular
diseases or osteoporosis [150, 153].
In women the serum cholesterol level was significantly reduced by soy intake. In peripubertal rhesus
monkeys, soy protein had favorable effects on plasma
lipid and lipoprotein concentrations [reducing very low
density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol in males and females and additionally increasing HDL cholesterol in females] without
affecting the reproductive system [154]. Similar observations were made in a non-human primate model of
post-menopausal women [155]. Soy has also proved to
prevent oxidation of LDLs in vitro when isolated from
soy-treated individuals. In normal cholesterolemic men,
no influences of protein supplementation (soy vs casein) could be observed on plasma total and HDL cholesterol, phospholipid polyunsaturated fatty acid composition, and platelet aggregation, however [156]. Other pulses (black gram, navy bean) were also linked to
hypocholesterolemic potency [157]. Ingestion of foods
rich in phytoestrogens (e.g. soy flour, red clover
sprouts, linseed, wheat flour) can lead to detectable effects in postmenopausal women (vaginal cell maturation, reduction of hot flushes) [158, 159]. However, in
an intervention study with 97 postmenopausal women
(one group receiving a soy supplemented diet for
4 weeks), only negligible estrogenic effects could be observed [160].
Isoflavones
The preventive effects of soy products have been related to their isoflavones content (Fig. 3). Reviews of
the clinical effects of phytoestrogens have been provided recently [161163]. Some effects are nevertheless
presented below.
It has been shown that genistein (4b,5,7-trihydroxyisoflavone) and daidzein (4b,7-dihydroxyisoflavone) inhibit the growth of human breast cancer and prostate
cancer cell lines [164, 165]. The preventive principle
seems to be due not only to the inhibition of the binding of steroids to their receptors, as growth inhibition
has been observed in ER-positive as well as in ER-ne-
Fig. 3 Structure of isoflavones
gative cell lines [166]. Thus, additional mechanisms

have to be assumed. Genistein is a potent inhibitor of
tyrosine-kinase, an enzyme which controls cell growth
and several signal processes. This enzyme inhibition
can lead to cell-cycle arrest and induction of apoptosis
in tumor cells [167]. Genistein also inhibits angiogenesis and has antioxidant properties [168, 169]. Furthermore, isoflavones stimulate the synthesis of sexual hormone-binding proteins, which may lead to a lower
bioavailability of endogenous steroid hormones [170,
171]. Further properties of genistein are the suppression of osteoclastic activity and reduction of bone loss
[172]. Daidzein rather than genistein is able to enhance
several immunologic functions and lymphocyte activation in animal (mice) and in vitro studies [173, 174]. In
mice, minimum doses of 8 mg/g diet genistein or 10 mg/g
diet daidzein were needed to induce a hormonal response [175]. To be able to achieve effects as postmenopausal hormone substituents (reduction of hot
flushes and vaginal dryness), daily doses of 0.5 mg isoflavones/kg body mass have to be ingested.
Occurrence of isoflavones in food. Soybeans are a rich
source of isoflavones (Table 10). The phytoestrogen
levels in soy products depend on plant variety, location,
harvesting year, and maturity [177]. Nevertheless, total
concentrations of genistein and daidzein (related to dry
weight) are similar in intact soybeans and soy products
except for soybean oil, soy sauce, alcohol-extracted soy
protein concentrate, and soy protein isolate (SPI). Isoflavones are not lost during defatting of fullfat soybeans
[181] or in manufacturing of tofu [176], but they are lost
during the SPI processing steps (alkaline) of extraction
(19%), precipitation (14%), and washing (22%) [194].
The loss strongly depends on the isolation procedures.
Previous studies showed a decrease of an original isoflavone concentration of 2870 mg/kg defatted soy flakes
to 2030 mg/kg after acid precipitation, to 530 mg/kg after dialysis, to 83 mg/kg after ion exchange, and to
61 mg/kg after active charcoal treatment [188].
The isoflavones mainly occur as their 7-O-glucoside
conjugates in nonfermented soy products, whereas fer-
166
Table 10 Concentrations of daidzein and genistein and their glucosides in soy food (mg/kg); meanBstandard deviation or range
Total daidzein
Soy bean
Soy powder
Soybean meal
Soy fluor
Soy seeds raw

Soybean roasted
Soybean toasted
Soybean hulls
Soybean pod
Soy fiber
Soybean flakes
Soy concentr.
Soy isolate
Soy protein
Soybean sprout
Soybean chips
Textured soy
Soy milk
Soy ice-cream
Soy drink
Soy formula
Tofu
Fermented tofu
Pressed tofu
Tofu yoghurt
Fermented curd
Soybean paste
Soy cheese
Tempeh
Miso
Rice miso
Soypaste/rice
Barley miso
Soypaste/wheat
Miso soup mix
Soy sauce
Soy hot dog
Soy noodle
Foo jook a
a
575B14
6761007
2060
754
341
206548
355B33
395488
434
355B49
658742
655
373950
674
789
226
90
913
546
786
563
860
~0.1
122
171B3
419B56
221
721
1165
911B66
43107
215271
250
633
225
267B58
568
473
74B6
81
335
7
18
49B2
7398
90137
113
258
139
146
250
136
163
57
90
224B33
14B2
211
137B15
273
366B28
71B2
155B16
272B22
162B17
208291
14B1
34
9
1160
Glucosides
91%
100%
7088%
59%
100%
9497%
4979%
50%
87%
97%
96%
5891%
6266%
76%
85%
6797%
;75%
8289%
12%
93%
18%
6%
0%
34%
32%
35%
4853%
0%
Total genistein
935B25
9401382
2040
1181
430
4571402
732B65
506695
2024
478B65
837939
1123
4031423
969
1069
810
92
763
729
889
869
852
18.4
144
210B9
1411B136
280
1222
1951
759B52
58211
374557
514
596
305
275B65
568
707
88B3
78
1839
21
22
87B3
187216
183187
166
377
141
162
288
139
190
94
192
300B17
20B2
383
235B22
320
524B32
260B7
149B18
336B21
193B19
337372
9B2
82
37
1317
Foo jook: skimmed dry supernatant obtained by boiling soybean material
Glucosides
93%
98%
7381%
47%
97%
9597%
6890%
59%
95%
96%
95%
6793%
6672%
81%
92%
7897%
;97%
8392%
16%
90%
30%
5%
48%
28%
29%
36%
5053%
0%
Comment/ref.
Asian
[176]
[177]
[178]
[179]
[180]
[181]
[176]
[182]
[183]
Asian
[176]
American
[176]
[177]
[184]
[185]
[186]
[187]
[177]
Dry
[186]
[187]
[186]
[187]
[186]
[177]
Green
[186]
[176]
Defatted
[188]
[189]
Defatted
[181]
Defatted
[190]
Water extracted [176]
alcohol extr.
[176]
[176]
[184]
[186]
[186]
[176]
[189]
[187]
[176]
[186]
[176]
[191]
[189]
[192]
[191]
[176]
[177]
[186]
[186]
[187]
[186]
[186]
Fried
[186]
[187]
[186]
[176]
[176]
[186]
[176]
[187]
[176]
[176]
[176]
[176]
[176]
[176]
[176]
[187]
Dry
[187]
Raw
[186]
167
daidzein and genistein in nonsoy food (mg/kg)
Black beans
Bean curd
Red beans
Broad beans
Small white beans
Green split peas
Kala chana
Flaxseed
Clover sprouts
Infant cereals
Candy bar
9-Grain bread
Crisp bread
Lapacho tea
Infant dinner a
Beer
a
Total
daidzein
Total
genistein
Comment/ref.
699
270
122
~0.1
~0.1
~0.1
72.6
~0.1
~0.02
~0.1
3287
0.52
0.08
~0.020.13
0.18
3145
0.020.6
612
277
307
3.1
12.9
7.4
~0.1
6.4
~0.02
3.5
2276
0.78
0.11
~0.020.10
0.29
3258
0.051.8
Dry
Boiled
Fried
Dry
Fried
Dry
Dry
Dry
[177]
[177]
[186]
[177]
[177]
[177]
[177]
[177]
[185]
[177]
[192]
[185]
[185]
[185]
[185]
[192]
[193]
Chicken and vegetable puree
mented soy foods contain predominantly aglycones

[176]. Whole soybeans contain large amounts of isoflavone 7-O-malonylglucoside conjugates [178]. Processing (e.g. toasting of soyflakes or fermentation) as
well as analysis (e.g. hot extraction) can induce decarboxylation and deesterification, resulting in 7-O-acetylglucosides, b-glucosides, or even the aglycones [176,
195, 196]. If available, the percentage of total glucosides
is given in the tables. However, in a number of studies,
just the total isoflavone concentration after hydrolysis
has been determined. In adults the glucosides can be
enzymatically hydrolyzed in the colon by the intestinal
flora, whereas aglucones are already resorbed from the
stomach and the upper intestinum [162]. The absorbed
isoflavones are (re)conjugated with glucuronic acid in
the liver to facilitate elimination.
Concern has been raised about feeding infants with
soy-based milk replacers because soy supplies considerable amounts of hormonally active compounds to the
newborn. However, soy based infant formulas often
contain lower isoflavone amounts (Table 10) because
they are generally prepared from SPI rather than from
whole soybeans [189]. Nevertheless, if newborns are
solely fed with soy products the isoflavone supply may
amount to 3 mg/kg body mass [192], which would exceed the amount that is needed to alter reproductive
hormones in adults. Some authors even estimated a
daily intake of isoflavones of 620 mg/kg [150, 197], but
others only of 0.10.3 mg/kg [198]. It also has to be considered that the glucuronidation potency of infant liver
is not yet fully developed, which might lead to a higher
bioavailability of isoflavones. Up until now, no adverse
clinical effects have been observable in infants fed with
soy products. On the other hand, phytoestrogens are
also discussed as having positive effects on newborns,
e.g. an improved resistence against some chronic diseases in adulthood [199, 200]. Further investigations
would be desirable to be able to evaluate the benefits
and risks of soy feeding to infants.
Isoflavones can also be supplied in small amounts

via cows milk or human milk. A single ingestion of soy
containing 35 mg isoflavones led to concentrations of
33 ng/ml daidzein and genistein in human milk [201].
Similar concentrations were measured in milk samples
of Chinese women regularly consuming soy products
[186].
Although the occurrence of flavonoids is widespread
in plants, only tropical legumes contain the enzyme
chalcone isomerase, which catalyzes the conversion of
2(R)-naringinen to the isoflavone 2-hydroxydaidzein.
Jones et al. [202] analyzed 107 food items on the British
market other than soy and could not detect any of these
phytoestrogens. In only a few non-soy foodstuffs have
genistein and daidzein been determined, mostly in other legumes or in cereals (Table 11).
Genistein and daidzein are not the only isoflavones
occurring in plant food that are hormonally active or
can lead to hormonally active metabolites. Glycitein (6hydroxymethyldaidzein, amounting to 20300 mg/kg in
soy food [186]) is not estrogenic [9], but the 4-methyl
ether derivatives of genistein and daidzein, biochanin A
and formononetin (Fig. 3), are weakly estrogenic
(binding affinity to ER, uterotrophic potency, and proliferative activity are 10 410 5 compared to 17b-estradiol). The biologically active dose of formononetin is
approximately 40 mg/kg (castrated female mice) [203].
Furthermore, biochanin A and formononetin can be
transformed by intestinal bacteria to biologically more
active substances. Biochanin A is converted to genistein, which is further metabolized to the hormonally
inert p-ethylphenol. Formononetin is converted to 4bO-methylequol or alternatively to daidzein, which is
further transformed to equol [7-hydroxy-3-(4b-hydroxyphenyl)chroman] or to O-demethylangolensin [1-(2,4dihydroxyphenyl)-2-(4-hydroxyphenyl)propan-1-one]
via dihydrodaidzein (Fig. 4) [204].
Equol is more estrogenic than genistein and daidzein. Absorbed equol is conjugated in the liver and ex-
168
Fig. 4 Structure of isoflavone metabolites
creted in the urine [205]. The same metabolism takes

place in ruminants. Equol has been identified in the
urine of cows, sheep, goats, rats, hens, and humans [9,
206]. The extent of isoflavone metabolism depends on
the individual intestinal flora, however. Equol has an
antagonistic effect on 17b-estradiol by competing with
the estradiol-receptor complex for nuclear binding
without effective replenishment of ER in the cytoplasma and without adequate stimulation of protein and
formononetin and biochanin
A in food (mg/kg)
Germinated bengal gram

Green beans
Large lima beans
Garbanzo beans
Kidney beans
Pinto beans
Small lima beans
Great northern beans
Broad beans
Pink beans
Black-eyed beans
small white beans
Yellow split peas
Chinese peas
Kala chana
Mung beans
Flax seed
Sunflower seeds
Clover sprouts
Alfalfa sprouts
Tofu
Soy drink
Textured soy
Soy flake
Soy flour
Soy formula
Candy bar
9-Grain bread
Crisp bread
Lapacho tea
Beer
a
n.d., not detectable
DNA synthesis [207]. Further mammalian metabolites

of isoflavonoid phytoestrogens (e.g. cis und
trans4b,7-dihydroxyisoflavan-4-ols) have to be expected [208]. Their properties are still unknown.
In contrast to daidzein and genistein, biochanin A
and formononetin were shown to have a hypolipidemic
effect in albino rats [209]. The occurrence of formononetin and biochanin A in different foodstuffs is presented in Table 12.
It has to be kept in mind that mammalian metabolites of isoflavones are also present in animal-derived
food (milk, meat) [212]. Concentrations in adipose tissue of sheep were reported to amount to 1 mg/kg
[213].
Isoflavones also have phytoalexin properties which
can lead to accumulation of these compounds in plants
[214]. This has to be considered for safety assessment of
the development of resistant plants. Isoflavones and
flavonoids also induce genes in plant-associated microbes (e.g. Rhizobiae) which are required for symbiotic association [215].
Other flavonoids
Estrogenic potency is not restricted to isoflavones,
however. Other flavonoids (chalcones, flavones, flavon-
Formononetin
Biochanin A
Ref.
770
440
1.5
0.1
~0.1
~0.1
~0.1
5.5
~0.1
2.1
10.5
~0.1
8.2
~0.1
~0.1
~0.1
6.1
~0.02
0.26
22.8
3.4
01
01
n.d. a
n.d.
0.30
n.d.
0.04
0.02
~0.020.03
0.08
0.054.5
710
970
~0.1
~0.1
15.2
4.1
5.6
3.7
6.0
~0.1
~0.1
17.3
~0.1
8.6
93.1
12.6
~0.1
~0.02
~0.02
4.4
~0.1
01
01
n.d.
n.d.
0.74
n.d.
0.02
~0.02
~0.02
0.36
0.21.4
[210]
[211]
[177]
Boiled [177]
[177]
Cooked [177]
[177]
[177]
[177]
[177]
[177]
[177]
[177]
[177]
Boiled [177]
[177]
[177]
[185]
[185]
[177]
[177]
[191]
[191]
[189]
[189]
[185]
[189]
[185]
[185]
[185]
[185]
[193]
169
at least 19 mg/day bioflavanoids has been linked to reduced mortality from coronary heart disease in elderly
men [221]. On the other hand, bioflavanoids are able to
inhibit the hepatic first-pass metabolism of 17b-estradiol and estrone, thereby increasing the amounts of
bioavailable estrogen [222].
Whereas isoflavones have been extensively investigated, little is known about the intake, bioavailability,
absorption, metabolism, and excretion of other estrogenic flavonoids.
Coumestans
Fig. 5 Structure of bioflavonoids
ol, flavanones) were also able to stimulate the transcriptional activity of the human ER (Fig. 5) [216]. The
most active flavanoids, besides genistein, daidzein, and
biochanin A, of 40 tested compounds were: 4,4b-dihydroxychalcone, isoliquiritigenin (2b,4,4b-trihydroxychalcone), phloretin (2b,4,4b,6b-tetrahydroxydihydrochalcone), 4b,5-dihydroxyflavone, 4b,6-dihydroxyflavone, apigenin (4b,5,7-trihydroxyflavone), kaempferol
(3,4b,5,7-tetrahydroxyflavone),
4b,7-dihydroxyflavanone, and naringenin (4b,5,7-trihydroxyflavanone)
(stimulation of transcriptional activity at least four-fold
above its basal level). The estrogenic potency was related to the hydroxylation pattern and correlated almost linearly with the relative affinity for ER [216].
Each ring of the diaryl ring structure had to have at
least one hydroxyl substituent, preferably in positions
4b and 7 of the flavan or isoflavan nuclei (equivalent to
positions 4 and 4b of chalcone). An additional
OH group in position 5 (position 2b, respectively) may
lead to increased estrogenic activity. Hydroxylations
that create catechols or that increase the number of hydroxyl substituents above four, or 4b-methoxylation,
appear to abolish estrogenic activity.
Some bioflavanoids such as quercetin (3,3b,4b,5,7pentahydroxyflavone), luteolin (3b,4b,5,7-tetrahydroxyflavone), or naringenin have been reported to possess
antiestrogenic properties (e.g. inhibition of estradiol-induced proliferation of MCF-7 human breast cancer
cells or uterine hypertrophy in female rats) by competing with estradiol for cytosol and nuclear type II binding sites [217, 218]. Recent studies revealed that some
flavonoids were even more potent inhibitors of cell
proliferation and in vitro angiogenesis than the isoflavone genistein, e.g. 3-hydroxyflavone, 3b,4b-dihydroxyflavone, 2b,3b-dihydroxyflavone, fisetin (3,3b,4b,7-tetrahydroxyflavone), apigenin, and luteolin [219]. Estrogenic activity and cell growth inhibition do not have to
correlate. Genistein has potent estrogen agonist and
cell growth inhibitory action over a wide concentration
range whereas other flavonoids can be good estrogen
agonists but poor cell growth inhibitors (equol) or vice
versa (kaempferol, quercetin) [220]. A dietary intake of
Coumestans are biosynthetically related to the isoflavones. Only a few coumestans possess uterotropic activity, the most common of which is coumestrol (7,12dihydroxycoumestan) (Fig. 6). The occurrence of coumestans in fodder crops has been associated with problems of animal performance. The estrogenic activity of
coumestrol is greater than that of the most potent isoflavones with respect to uterine gland development and
influence on ER levels (approximately 10 110 3 times)
[175, 223, 224]. The affinity to ER is approximately
10% compared to 17b-estradiol [17, 225, 226].
At natural dietary concentrations, coumestrol acted
mainly as an estrogen agonist in the reproductive tract,
brain, and pituitary of immature female rats, but antiestrogen actions (suppression of estrous cycle) have also
been observed [227]. Orally administered coumestrol
did not support the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumors, nor
did coumestrol act as an antiestrogen when administered together with 17b-estradiol [228, 229]. Oral or
subcutaneous treatment with coumestrol led to increased cytosolic ER without corresponding cytosol depletion and nuclear accumulation of this receptor in the
rat uterus, resulting in an increased sensitivity to subsequent stimulation by estradiol [230]. Coumestrol does
not increase uterine DNA content, however, which
would normally be characteristic for estrogen action
[230]. Lactational exposure to coumestrol led to deficits
in neuroendocrine development in both male and female rats (without reducing plasma testosterone levels)
[231]. A further property of coumestrol is the stimulation of bone-mineralizing activity, which has been demonstrated in organ culture [232] and animal models
[233].
Fig. 6 Structure of coumestrol
170
coumestrol in food (mg/kg)
Clover sprouts
Soybean sprouts (fresh)
Alfalfa sprouts (fresh)
Round split peas
Kala chana seeds
Pinto beans
Large lima beans
Soybeans
Soybean meal
Soy flour
Soybean concentrate
Sobean isolate
Textured soy
Soy flake
Tofu
Soy drink
Soy formula
Green beans
Snow beans
Green peas
Brussels sprouts
Red beans
Split peas
Spinach leaf
a
Coumestrol
Ref.
281
71.1
;12.1
4.59.2
46.8
5.0
81.1
61.3
36.1
14.8
1.2
0.4
~0.02
0.2
0.6
n.d. a
n.d.
01
01
n.d.
1.0
0.6
0.4
0.4
0.4
0.3
0.1
[177]
[234]
[234]
[180]
[177]
Dry wt.
[234]
Dry
[177]
Dry
[177]
Dry
[177]
Dry
[177]
Dry wt.
[234]
Defatted, dry wt. [234]
[185]
Dry wt.
[234]
Dry wt.
[234]
[189]
[189]
Wet wt.
[191]
Wet wt.
[191]
[189]
Frozen, dry wt. [234]
Dry wt.
[234]
Dry wt.
[234]
Dry wet.
wet wt.
n.d., not detectable
Lignans
metabolizing enzymes such as 5a-reductase, 17b-hydroxysteroid dehydrogenase or aromatase and stimulate the synthesis of SHBG [240243]. In rat mammary
and colon tumorigenesis studies, ingestion of flax seed
revealed at initiation and promotion stages a cancer
protective role (reduction of tumor incidence, numbers
and size, cell proliferative indices, and total number of
aberrant crypts and foci) [244, 245]. Enterolactone,
however, can stimulate growth of estrogen-dependent
breast cancer cell lines [246]. The biological effects of
The two major mammalian lignans, enterodiol and enterolactone, are the products of colonic bacterial metabolism of the plant lignans secoisolariciresinol
([R(R*,R*)]-2,3-bis[(4-hydroxy-3-methoxyphenyl)methyl]-1,4-butanediol) and matairesinol [(R-trans)-dihydro-3,4-bis[(4-hydroxy-3-methoxyphenyl)methyl]-2(3H)
-furanone] (Fig. 7). These weakly estrogenic lignans
also occur as glycosides. Dietary sources are flax seed,
whole grain products, fruits, vegetables, and tea (Table 14). In grain the lignans are located in the aleuric
layer [185]. Therefore, intake of isolated wheat germ,
bran, and white flour does not lead to significant mammalian lignan production [238]. Intake of flax seed
causes the highest production of mammalian lignans
[237]. The lignan concentrations in the human can exceed the endogenous concentrations of steroid hormones up to 1000 times.
Some lignans have antioxidative properties [239].
Consumption of food that contains lignans has been negatively correlated with coronary heart disease [236].
Lignans as well as isoflavones inhibit steroid hormone
Fig. 7 Structure of plant lignans and mammalian lignan metabolites
In human diet, coumestrol occurs predominantly in

legume shoots and sprouts (Table 13), which have
gained increasing popularity in recent years. Coumestrol has been observed to accumulate in legumes following insect or fungal attack [235]. Contents of coumestrol in animal products obtained from livestock
grazing on estrogenic pasture are still unknown.
171
lignans in plants and production of mammalian lignan
from different foods (mg/kg)
Secoisolariciresinol
Cereal brans
Candy bar
9-Grain bread
Crisp bread
Rye bread
Flax seed
Defatted flax seeds
Other soil seeds
Sunflower seeds
Tea
Lapacho tea
Legumes
Soy fluor
Vegetables
Fruits
Matairesinol
Enterodiolc
enterolactone
[237]
1.159.24
0.21 [185]
0.71 [185]
0.280.42 [185]
11.5 [185]
3700 [185]
0.40 [185]
0.11 [185]
0.520.62 [185]
0.57 [185]
10.87 [185]
6.1 [185]
5.628.9 [236]
26.7 [185]
~0.02 [185]
0.564.13 [236]
16.7 [185]
lignans and phytoestrogens on cell culture growth and

enzyme activity are summarized in a review published
recently [247].
Phytosterols
A further group of plant-derived compounds which are
linked to estrogenic effects are phytosterols. The consumption of plant sterols has been estimated to be
160360 mg/day in Western diets [248]. The most abundant phytosterols in nature are b-sitosterol, campesterol, stigmasterol, and dihydrobrassicasterol. They are
not only natural constituents of foodstuffs but are also
present in wood and therefore in pulp and paper mill
effluents, which show weak estrogenicity. The estrogenic compound in these effluents was determined as bsitosterol [249]. Bourbon whiskey, which contains b-sitosterol in addition to biochanin A, showed estrogenic
activity in a bioassay with oophorectomized rats [250].
Technical formulations of b-sitosterol show less estrogenicity than natural extracts from soybeans [251]. This
sterol seems to reduce gonadal steroid biosynthetic capacity through effects on cholesterol availability or the
activity of the side-chain cleavage enzyme cytochrome
P450 [252].
Similar to other phytoestrogens, plant sterols have
been shown to reduce plasma total and LDL cholesterol levels [248]. This ability is probably due to a reduced intestinal absorption of cholesterol [253]. The
most potent sterol seems to be sitostanol, a non-absorbable, non-estrogenic 5a-saturated sitosterol derivative
[254, 255], particularly if administered in esterified formulations [256]. Consumption of margarine containing
sitostanol esters significantly reduced serum cholesterol
levels in a mildly hypercholesterolemic population as
well as in children with familiar hypercholesterolemia
[257, 258]. Addition of sitostanol to the diet (approx.
3 g/day) has therefore been recommended by some authors for improving blood lipid profiles and reducing
the risk of coronary heart disease [248].
527
675
1.6111.3
2.0112.87
1.3 [185]
~0.02 [185]
0.214.07
0.351.81
A recent study revealed, however, that margarine

containing esters of sitosterol, campestrol and stigmasterol obtained from soybean oil was also able to reduce
blood total and LDL cholesterol in the blood of normocholesterolemic and mildly hypercholesterolemic individuals [259].
Concluding remarks on phytoestrogens
Safe [218] estimated the daily intake of estrogen equivalents via flavanoids to 102 mg, assuming an intake of
total flavanoids of 1020 mg (according to [260]) and an
average estrogenic potency of 10 4compared to 17b-estradiol. However, the dietary intake of isoflavones in
Asia, where large amounts of soy foods are consumed,
has been estimated to be only 25100 mg/day [176].
This would result in an intake of estrogen equivalents
of 2.510 mg/day via isoflavones (for comparison, the
estimated intake of estrogen equivalents via steroidal
estrogens is 0.1 mg/day [11]). The daily intake of phytoestrogens will vary widely, however, depending on individual consumption habits.
It should be noted that phytoestrogens can act as estrogen antagonists but also as real estrogens, depending
on the hormonal environment. In the presence of more
potent estrogens, anti-estrogenic properties occur [261].
In low-estrogen environments, phytoestrogens (e.g.
coumestrol, genistein, biochanin A, apigenin, luteolin,
kaempferol, and enterolactone) lead to enhanced DNA
synthesis and stimulation of cell proliferation in estrogen-dependent cancer cells (MCF-7) but not in independent cancer cells (MDA-MB-231) [166]. Concern
has been raised, for instance, that phytoestrogens could
be endocrine disruptors in males [262]. A fact that
might lead to an improved bioavailability of phytoestrogens compared to endogenous hormones is the only
weak binding to the sex steroid-binding globulin [228].
Phytoestrogens proved to be non-mutagenic when
screened using the Salmonella/mammalian microsome
assay [263]. However, coumestrol and also genistein
172
have been identified as potent clastogens in mammalian cell cultures, whereas daidzein, enterolactone, and
enterodiol did not exert genotoxic properties [264, 265].
Coumestrol also showed mutagenicity in Chinese hamster V79 cells [264]. The evaluation of hydroxylated lignan metabolites has not been performed yet.
From the above it may be concluded that recommendations with regard to the intake of dietary estrogens should be made with caution. Particularly the proportion of those estrogens with comparably high estrogenic potency and known adverse effects, such as
coumestrol, should not be generally enhanced in nutrition, e.g. by genetic engineering. These compounds
should be regarded as and controlled as pharmaceuticals. Their administration might be beneficial in some
particular cases (e.g. for bone diseases or in cancer
therapy) but contraindicated for other sections of the
population.
Other food constituents with hormonal activity

Foodstuffs contain a wealth of endocrinologically active
compounds. A number of plant constituents, including
stilbenes such as resveratrol, have been linked to estrogenicity [8, 9]. A particularly well documented animalderived foodstuff is milk, which contains besides sex
and adrenal gland hormones a multiplicity of neuropeptides, growth factors, hypothalamo-hypophyseal
hormones, thyroid and parathyroid hormones, pancreatic and brain-gut hormones. A comprehensive review is provided by Koldowsk [266].
The presentation of all kinds of dietary hormones
would be beyond the scope of the present review. Thus,
only a selected number of hormones with sex hormone
antagonistic or growth related properties will be addressed, namely the glucocorticoids, the anti-estrogen
indole-3-carbinol, and the growth related protein hormones.
milk is higher than the cortisol level [266]. Cortisol

reaches about 1.75B0.38 mg/l in milk from non-pregnant cows and 0.91B0.11 mg/l in milk from pregnant
cows, whereas corticosterone amounts to 2.58B0.39 mg/
l and 3.46B0.54 mg/l, respectively [76].
Cortisol concentrations in muscle tissue of bulls and
steers were reported to be 6.52B5.16 mg/l and
10.62B8.33 mg/l, respectively [49]. Similar results have
been obtained by Fritsche et al., who determined mean
concentrations of 4.5 mg/kg cortisol, 2.5 mg/kg cortisone, and 0.2 mg/kg corticosterone in beef from bulls
and 6.0 mg/kg cortisol, 2.0 mg/kg cortisone, and 0.2 mg/
kg corticosterone in beef from steers (S. Fritsche et al.,
unpublished results). Besides these corticosteroids, 11dehydrocorticosterone, 11-deoxycorticosterone, and
11-deoxycortisol have also been determined in amounts
of 0.10.7 mg/kg.
Cortisol concentrations in muscle juice of pigs were
reported to be 30B2 mg/l for animals from a fat line
and 34B2 mg/l for animals from a selected lean line
[269]. No differences could be observed between male
and female pigs. Carcasses classified as dark, firm and
dry had significantly higher muscle cortisol concentrations than those classified as normal (P~0.05).
Corticosteroids have also been detected in plants
[102, 270].
Indole-3-carbinol
Indole-3-carbinol (Fig. 8) is an anti-estrogen present in
cruciferous vegetables (e.g. cabbage, broccoli) which
have also been linked to anticarcinogenic properties
[271]. Oral administration of indole-3-carbinol induces
2-hydroxylation of endogenous estrogens in humans,
thereby leading to a decrease of active estrogens. This
results in an inhibition of tumor growth [272].
Protein hormones
Corticosteroids
Corticosteroids are also natural constituents of food.
The predominant glucocorticoids are cortisol, which
can be converted to cortisone in the body (Fig. 1), and
corticosterone. These compounds exhibit glycogenic
and protein catabolic activity and they can control inflammatory processes. Corticosterone seems to play a
preventive role in the inhibition of mammary carcinogenesis due to caloric restriction [267].
The occurrence of glucocorticoids is known in meat
and milk. In contrast to the lipid-associated sex steroids, the more polar glucocorticoids are associated primarily with the protein fractions of milk [76]. Therefore, the concentration of total corticosteroids is the
same in whole and skim milk [268]. Fat-associated glucocorticoids are located on the fat globule membrane.
In contrast to plasma, the corticosterone level in bovine
Protein hormones are also under discussion, particularly bovine somatotropin (BST), which has been authorized in more than 20 countries, but not in the EU, to
improve milk production of dairy cattle. The growth
hormone BST is a natural constituent of all bovine
meat and milk. If protein hormones are ingested by humans they are digested in the gastro intestinal tract to
non-active proteolysis products. Furthermore, protein
hormones have a narrow species range of activity [273].
Fig. 8 Structure of indole-3-carbinol
173
However, treatment with BST can lead to elevated levels of insulin-like growth factor-1 (IGF-1), a non-species-specific intermediary which has been linked to increased growth of breast cancer cells [274]. Residual
levels of growth hormone (110 mg/l milk, 210 mg/kg
muscle, 1030 mg/kg liver) and/or IGF-1 (520 mg/l
milk, 75450 mg/kg muscle, 75200 mg/kg liver) did not
differ significantly in treated and untreated animals
(cattle and pigs), however [275]. It can be concluded
that additional hormonal activity by growth hormones
cannot be expected. However, the composition of meat
and milk may be influenced by BST [276].
Thyrotropin, however, is biologically active in humans. Incidences of thyrotoxicosis have been reported
after ingestion of beef which was probably contaminated with thyroid glandular tissue [277].
Further influences of diet on human

endocrine functions
Intake of hormonally active compounds can be one factor which may affect the human endocrine system. Visible effects can be observed if either large amounts of
weak hormone agonists or antagonists are ingested or if
highly active compounds are administered (as can be
seen in cases of doping in sports). In this context it
should be noted that almost nothing is known about the
occurrence of lipophilic derivatives of hormones, particularly fatty acid esters, in food. These compounds
would not be detected with routine analytical procedures but would have higher oral activity than non-esterified hormones. In human circulation, considerable
amounts of lipophilic esters of hormone precursors
(pregnenolone, DHEA) have been reported [278,279].
However, if only small amounts of orally weak hormones are ingested, hardly any effects can be expected.
Generally, the individual is able to buffer variations in
hormone exposure. It has been shown that changes in
total plasma hormone concentration result in relatively
small changes in the size of free hormone fractions because a large percentage of the available SHBG binding sites are usually unoccupied [280]. The proportion
of free (i.e. bioavailable) hormones may be of more importance to health than total hormone concentrations.
Levels of free circulating estrogens are, for example,
higher in breast cancer patients than in healthy controls
[281, 282]. A high-fiber diet may have protective effects
because of its increase of plasma SHBG levels, which
can reduce the proportion of bioavailable hormones
[283]. Additionally, dietary fiber has been shown to
bind estrogens in the gut and increase their fecal excretion [284]. Consequently, fiber intake correlates negatively with plasma estradiol, estrone, androstenedione
and testosterone [285, 286]. Similar correlations are observed with carbohydrate intake. In a case control and
an epidemiological study it was shown that high fiber
and high carbohydrate intake, respectively, decreased
the risk of breast cancer [287, 288]. Suppression of
mammary gland tumorigenesis by wheat bran fiber has

also been shown in animal models [289]. The protein/
carbohydrate ratio also correlates with plasma hormone levels and hormone metabolism. A high ratio decreases plasma SHBG and testosterone [290, 291]. Furthermore, a high protein diet diminishes 4-ene-5a-reduction of testosterone and enhances 2-hydroxylation
of 17b-estradiol [292, 293]. The ratio of polyunsaturated to saturated fat also affects plasma androgen and
estrogen levels [294, 295]. A vegetarian diet seems to be
associated with relatively high estriol formation in women and with a lower b-glucuronidase activity of the
intestinal bacteria [238, 296]. The latter reduces reabsorption of the free hormones [297]. Another influence
on endogenous hormone levels can be alcohol consumption. Ethanol has several effects on androgen production and metabolism [298]. Acute alcohol intake can
lead to increased plasma levels of adrenal androgens
(androstenedione, DHEA, testosterone) and corticoids
[299]. Furthermore, extragonadal conversion of androgen precursors to testosterone is enhanced and metabolism via cytochrome P450 is inhibited [298]. Alcohol-induced increase of aromatization can lead to higher estrogen levels in postmenopausal women [300].
Diet influences hormone levels, but the opposite is also
true: hormone levels can influence appetite, food intake, and macronutrient selection [301].
Residues and contaminants exhibiting hormonal or

hormone-blocking activity
Hormonally active compounds are not only naturally
present in foodstuffs; residues of industrial chemicals or
pesticides, or metabolites of microorganisms which
have infected foodstuffs, may also act as hormone mimics or antagonists. These substances also contribute to
the human exposure to hormonally active compounds.
Mycoestrogens
Zearalenone is a resorcylic acid lactone (Fig. 9) produced by the commonfield fungus Fusarium which can
also infect stored grains, oil seeds, and hay [9]. It has
relative binding affinities to ER (MCF-7 cells) similar
to coumestrol, whereas the reduced derivative zearale-
Fig. 9 Structure of zearalenone
174
nol (a-isomer) has even greater affinities [228, 229].

The levels of zearalenone in grain crops vary widely.
They range from not detectable (~10 mg/kg) to
100 mg/kg [9]. The distribution of zearalenone in
starch, fiber, germ, and protein fraction depends on the
milling process [302, 303]. Zearalenone may also be detected in food processed from grains, e.g. beer [304].
Hormonal effects could be noted in pigs with a
15 mg/kg zearalenone diet [305, 306]. Feeding contaminated grain to cattle did not lead to zearalenone residues 1 4 mg/kg in muscle, liver, kidney, or milk [307].
However, most of the original compound is metabolized to zearalanols (in ruminants mainly a, in non-ruminants mainly b) [308310]. In primates, orally administered zearalenone was 80 times less active than 17bestradiol [311]. In humans, 5075 mg/day are clinically
effective in the treatment of postmenopausal syndrome
in women [312]. However, doses of 500 mg/kg are already considered biologically active [313]. The daily intake
of zearalenone has been estimated to be 170 mg for inhabitants of Lusaka [304].
Environmental estrogens
A great number of industrial chemicals show estrogenic
effects, including organochlorine pesticides, heavy metals, polychlorinated biphenyls, alkylphenols, dibenzodioxins, dibenzofurans, stilbenic brighteners, or phthalates. These compounds may be ingested via contaminated foodstuffs or water. Some examples are given in
Table 15. These environmental estrogens show sig-
nificantly lower estrogen equivalents than 17b-estradiol. Furthermore, they are taken up in only very minute amounts. The maximum exposure to pesticides, for
example, has been estimated to be 2.5 mg/day and the
exposure to dioxines and organochlorines to 100 pg/day
[218]. However, the bioavailability of these xenoestrogens is not regulated by transport proteins. The effectiveness may also be increased by synergistic effects
[320]. Furthermore, lipophilic xenoestrogens may be
accumulated in fatty tissues. Accumulation of alkylphenols in adipose tissues of fish of up to 40 mg/kg have
been reported, for example. Some studies indicated the
occurrence of higher concentrations of DDE and PCB
in lipids of breast cancer patients than of healthy controls [321]. Other studies could not confirm a positive
correlation between organochlorines and risk of breast
cancer, however [322].
Xenoestrogens may not only act through the classic
pathway of binding and activating ER. For example, bHCH stimulates proliferation in ER positive but not in
ER negative cell lines [323]. However, this compound is
not able to displace 17b-estradiol from ER. Some xenoestrogens (atrazin, chlordecon, DDT, DDE) increase
16-hydroxylation of 17b-estradiol and decrease 2-hydroxylation, which is linked to an increased risk of
breast cancer [324].
A famous industrial estrogen is bisphenol A (4,4bisopropylidenediphenol), a component of polycarbonates and of resins used to line metal food cans. Its estrogenic activity was already recognized in 1936 [325].
Bisphenol A might get into foodstuffs via migration
from packaging [326]. Concentrations up to 33 mg/can
Table 15 Chemicals with nendocrine effects [314]

Compound
Function
Effect
Aldrin, dieldrin
Atrazin
Dicofol
DDE
DDT
Endosulfan
Heptachlor
Hexachlorocyclohexane
Chlordecone
Methoxychlor
Phosmet
Toxaphene
Benzophenone
t-Butylhydroxyanisole (BHA)
Bis(2-ethylhexal) adipate (DEHA)
Bisphenol A (dimethacrylate)
Phthalates (DBP, BBP)
Alkylphenols
Polychlorinated biphenyls (PCB)
Coplanar congeners
2,4-Dichlorphenol
Dibenzodioxins, dibenzofurans
Polycyclic aromatic hydrocarbons (PAH)
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide
Pesticide, UV absorber
Antioxidant
Plasticizer
Plastics monomer
Plasticizer
Surfactant educt
Isolator, coolant
Estrogen
Estrogen
Estrogen
Anti-androgen
Estrogen
Estrogen
Estrogen
Estrogen
Estogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Estrogen
Anti-estrogen
Estrogen
Anti-estrogen
Anti-estrogen
Industrial intermediate
Toxic pollutant
toxic pollutant
a
Estimated (relative to 17b-estradiol) on affinity to estrogen receptor, proliferative effect on MCF-7 breast cancer and anterior
pituitary cells, transcriptional activity of human ER, induction of
Estrogen
equivalent a
10 P7
10 P7
10 P6
10 P610 P7
10 P310 P4
10 P6
10 P310 P4
PR in MCF-7 cells, and prolactin gene expression and release

[315319]
175
(corresponding to approximately 80 mg/kg canned

food) have been determined in the liquid phase of vegetables packed in laquer-coated cans. Migration of bisphenol A also disturbed experiments screening for estrogenic activity of cells cultured in media containing
water that had been autoclaved in polycarbonate flasks
[315]. Bisphenol A and some of its analogs have an
aneuploidogenic potential [327]. A daily dosage of 2 mg
bisphenol A/kg body mass given to pregnant mice led
to significant biological effects in the male offspring
(enlargement of the prostate) [328]. The daily intake of
bisphenol A has been estimated to a maximum of 1 mg/kg
body mass [329].
Phthalates can also migrate from food wraps (e.g.
cellulosics, PVC). Reported levels of di-n-butyl phthalate (DBP) in food range from 50 mg/kg up to 14 mg/kg
[318]. The daily intake of phthalates is in the same order of magnitude as that of bisphenol A [329]. BHA is
commonly used as antioxidant in food. Its daily intake
has been estimated to be approximately 0.13 mg/kg
body mass [330].
Only few chemicals are known so far to possess androgenic potency. Exceptions are the fungicide vinclozolin and ppb-DDE (the latter binds to AR approximately 10 6 compared to testosterone). No binding to
PR has yet been observed [316]. A great number of
chemicals will still have to be screened for hormonal
activity or cumulative or synergistic effects when combined with hormonally active compounds. Estimates indicate that as many as 7!10 5 chemicals will have to be
tested [331]. Unfortunately, it cannot be deduced from
the molecular structure which chemicals are hormonally active, and implications for human health will depend entirely on the hormonal potencies in vivo because screening tests cannot resemble human metabolic
transformation and bioaccumulation.
Acknowledgements The authors wish to thank Dr. Jan Fritsche
and Gabi Schmidt for reviewing this manuscript.
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Occurrence of Hormonally Active Compounds in Food A Review

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Occurrence of Hormonally Active Compounds in Food A Review

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Eur Food Res Technol (1999) 209 : 153179

Sonja Fritsche 7 Hans Steinhart

Occurrence of hormonally active compounds in food: a review

Received: 12 August 1998 / Revised version: 3 November 1998

Abstract The present review gives an overview of the

S. Fritsche 1 7 H. Steinhart (Y)

Key words Hormones 7 Food 7 Steroids 7

Mammalian sex hormones

proteins, e.g. albumin or sex hormone-binding globulin

Androgens and progestins

adrenal androgens can be converted to testosterone (or

Occurrence of steroid hormones in food

0.3 (~0.30.4) [45]

18.9 (5.843.7) [45]

0.5 (~0.22.8) [45]

~0.01 [50, 51]

0.4 (~0.31.7) [45]

0.02B0.00 [39, 51]

process. Natural progesterone concentrations range

Anabolic steroids as performance enhancers

hormones in meat from treated cattle are well within

Fat reduced milk

Liver and fat of barrows and gilts show equivalent

Steroid hormones in poultry and eggs

0.03 (0.000.16) [78]

0.32 (0.150.44) [78]

0.09 (0.000.23) [78]

[79], quartile (2575%)

male broilers and up to 0.02 mg/kg in turkey toms.

Steroid hormones in fish

roid hormones, fish-specific hormones such as 11b-hydroxyandrostenedione, 11-ketoandrostenedione, and

Melted from goose

Steroid hormones in plants

Their biosynthesis may start from the same precursors

Steroid hormones in drinking water

Dietary intake of steroid hormones

?, not interpretable owing to interferences

Occurrence of steroid hormone precursors in food

sides, numerous human peripheral tissues (e.g. skin, fat,

0.67 (0.352.37) [46]

0.24 (0.081.51) [46]

0.39 (0.040.78) [46]

1.24 (0.313.07) [46]

0.19 (0.080.53) [46]

0.24 (0.050.92) [46]

2.8 (1.06.5) [45]

~0.2 (~0.20.6) [45]

0.3 (~0.24.3) [45]

Melted from goose

Pregnenolone is the basic precursor for all kinds of

individual. In environments with low or no estrogen,

Non-steroid dietary hormone mimics or antagonists

and mortality from breast cancer compared to the

Fig. 3 Structure of isoflavones

gative cell lines [166]. Thus, additional mechanisms

Soy seeds raw

Foo jook: skimmed dry supernatant obtained by boiling soybean material

Chicken and vegetable puree

mented soy foods contain predominantly aglycones

Isoflavones can also be supplied in small amounts

Fig. 4 Structure of isoflavone metabolites

creted in the urine [205]. The same metabolism takes

Germinated bengal gram