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Nutr Influences Estrogen
Nutr Influences Estrogen
ABSTRACT: It is now well known that one of the most promi- estrogen metabolism can be accomplished through dietary and
nent causes of breast cancer, as well as many other hormone lifestyle modifications such as increasing fiber and reducing fat,
related health problems in both men and women, is excessive increasing phytoestrogen intake, losing weight, and increasing
estrogen exposure from both endogenous and exogenous exercise. In addition, many nutrients effectively reduce estrogen
sources. Improving estrogen metabolism can be of benefit in load by supporting preferred pathways of estrogen metabolism
women with various conditions and family histories, including a and detoxification, including indole-3-carbinol, B vitamins,
family history of breast, uterine, or ovarian cancer, and condi- magnesium, limonene, calcium D-glucarate, and antioxidants.
tions such as endometriosis, premenstrual syndrome, uterine The influences of these nutrients on estrogen metabolism may
fibroid tumors, fibrocystic or painful breasts, cervical dysplasia, have profound significance for diseases in which these hor-
and systemic lupus erythematosis. Beneficial modulation of mones may play a role in clinical expression.
ESTROGEN PRODUCTION cells and induce biological activity.1,2 This is an important point,
because it means that any change in the concentration of SHBG
The term “estrogen” is used to collectively describe the will alter estrogen metabolism by inducing changes in the avail-
female hormones, the most potent of which is estradiol. The ability of estrogen to the target cell.
other important—but less powerful—estrogens are estrone and
estriol. Estrogens affect the growth, differentiation, and function ESTROGEN METABOLISM AND DETOXIFICATION
of diverse target tissues—not only those involved in the repro-
ductive process, but tissues throughout the body. Estrogens play Metabolism of estrogen within the body is a complex and
an important role in bone formation and maintenance, exert car- important subject (Figure 1). Estrone and estradiol are biochem-
dioprotective effects, and influence behavior and mood. ically interconvertible and yield the same family of estrogen
Although estrogen is best known for its critical role in female metabolites as shown for estrone in Figure 1. Because these
reproduction, less well known are the important actions of estro- metabolites vary greatly in biological activity, the ultimate
gen in male tissues, such as the prostate and testes.1,2 biologic effect of estrogen depends on how it is metabolized. The
metabolism of estrogen takes place primarily in the liver through
In women, estrogens are synthesized from cholesterol in the Phase I (hydroxylation) and Phase II (methylation, glucuronida-
ovaries in response to pituitary hormones. In an adult woman tion, and sulfation) pathways with ultimate excretion in the urine
with normal cycles, the ovarian follicle secretes 70 to 500 µg of and feces.1
estradiol per day, depending on the phase of the menstrual cycle.
Estradiol can be converted to estrone and vice versa, and both • Hydroxylation
can be converted to the major urinary metabolite, estriol. Cytochrome P-450 enzymes mediate the hydroxylation of
Estrogens are also produced by the aromatization of androgens in estradiol and estrone, which is the major Phase I metabolic
fat cells, skin, bone, and other tissues. After menopause, most pathway for endogenous estrogens. This takes place at two
endogenous estrogen is produced in the peripheral tissues by the primary sites on the estrogen molecule, either at the 2 carbon
conversion of androstenedione, which is secreted by the adrenal (C-2) position yielding 2-hydroxyestrone (2-OH) or at the
cortex, to estrone. In addition, some estrogen continues to be 16α carbon (C-16α) position yielding 16α-hydroxyestrone
manufactured by aromatase in body fat, and the ovaries continue (16α-OH). A minor contribution is made from hydroxylation at
to produce small amounts of the male hormone testosterone, the 4 carbon (C-4) position yielding 4-hydroxyestrone (4-OH).3
which is converted to estradiol. The total estrogen produced after The 2-OH metabolite confers very weak estrogenic activity, and
menopause, however, is far less than that produced during a is generally termed the “good” estrogen. In contrast, the 16α-OH
woman’s reproductive years.1,2 and 4-OH metabolites show persistent estrogenic activity and
promote tissue proliferation.3-6 It is suggested that women who
Estradiol and other naturally occurring estrogens circulate in metabolize a larger proportion of their endogenous estrogen via
the body bound mainly to the sex hormone binding globulin the C-16α hydroxylation pathway may be at significantly elevat-
(SHBG); however, only unbound estrogens can enter target-tissue ed risk of breast cancer compared with women who metabolize
1
proportionally more estrogen via the C-2 pathway.3-5,7-9 This helps to explain how phytoestrogens and the new designer
Furthermore, it is theorized that shifting estrogen balance toward estrogen drugs such as tamoxifen and raloxifene—called
a less estrogenic state through promotion of the C-2 pathway selective estrogen receptor modulators (SERMs)—behave like
may prove beneficial for a variety of conditions related to estro- estrogens in some tissues but block its action in others.
gen dominance or imbalance. Unraveling the detailed physiological role of each receptor
subtype is needed to further elucidate the complex nature of
• Methylation estrogen’s mechanisms of action.
The 2-OH and 4-OH metabolites (catechol estrogens) are
readily oxidized to quinones, which are highly reactive and can ESTROGEN AND CANCER
damage DNA and promote carcinogenesis directly or indirectly
through the generation of reactive oxygen species. This harmful Epidemiological and animal studies have identified estrogen
pathway can be minimized through preferential detoxification exposure as a risk factor for several cancers, namely breast,
and excretion of the catechol estrogens via Phase II methylation endometrium, ovary, prostate, testis, and thyroid. Much of the
by the catechol-O-methyltransferase (COMT) enzyme.5,10,11 This evidence comes from the observation that cancer risk increases
methylation requires S-adenosylmethionine (SAM) and magne- with increased exposure to endogenous or exogenous estrogens,
sium as cofactors.11 COMT is present in most tissues and and the positive relationship observed between blood levels of
converts catechols into their corresponding methyl ester estrogens and cancer risk.7,18-22 Prolonged estrogen exposure can
metabolites, which are more water soluble.5,7 Recent data cause direct genotoxic effects by inducing cell proliferation in
suggest that the methylation of 4-OH renders this harmful estrogen-dependent target cells (increasing the opportunity for
metabolite significantly less active, while 2-methoxyestrone the accumulation of random genetic errors), affecting cellular
may manifest beneficial properties by inhibiting breast differentiation, and altering gene expression. Additionally, there
cancer.10,12 Therefore, supporting the methylation pathways is increasing evidence for indirect genotoxic effects of estrogens
promotes detoxification of estrogens and provides for more as well. The relative importance of each mechanism is likely a
beneficial metabolites of estrogen. function of the specific estrogen, as well as the exposed tissue or
cell type and its metabolic state.5,7
• Glucuronidation
Direct Genotoxic Effects
Glucuronidation is one of the key Phase II liver detoxifica-
tion pathways for estrogens and other toxins. Glucuronic acid is Evidence is accumulating that some estrogen metabolites may
conjugated with the estrogen to facilitate its elimination from the be directly responsible for the initial genetic damage leading to
body.1 Unfortunately, some intestinal bacteria (mostly pathogen- tumors. 16α-OH and 4-OH are the primary estrogen metabolites
ic) possess an enzyme, β-glucuronidase, that uncouples the bond that have been associated with direct genotoxic effects and
between excreted estrogen and glucuronic acid in the large intes- carcinogenicity.5,7 Some researchers believe increased levels of
tine, allowing the estrogen to reenter circulation (enterohepatic 16α-OH may increase the risk of breast cancer by increasing both
recirculation).13 Not surprising is the finding that excess cell proliferation and direct DNA damage; however, scientific
β-glucuronidase activity is associated with an increased cancer consensus has not yet been reached.5,7-9,23 Conversely, 2-OH may
risk, including breast cancer.14 The activity of β-glucuronidase is induce apoptosis and thereby inhibit cell proliferation, an impor-
increased when the diet is high in fat and low in fiber, and can tant mechanism in the prevention of cancer.12
be reduced by establishing a proper bacterial flora by eating a
diet high in plant foods and supplementing the diet with the A recent 5-year prospective study of 10,786 women was
“friendly bacteria” Lactobacillus acidophilus and conducted to investigate the role of estrogen metabolism as a
Bifidobacterium infantis.15 predictor of breast cancer, specifically the ratio of 2-OH to
16α-OH.4 The researchers found that premenopausal women
ESTROGEN RECEPTORS who developed breast cancer had a decreased 2-OH:16α-OH
ratio and a higher percentage of 16α-OH than 2-OH. Women
Estrogens, like all steroid hormones, have a wide range of with predominately 2-OH were 40% less likely to have devel-
actions and affect almost all systems in the body, yet act in a oped breast cancer during the 5 years. Another recent case-
tissue-specific manner. Estrogens act by binding with high affin- control study that began in 1977 found that postmenopausal
ity to the estrogen receptor (ER) in target cells. Once bound by women who developed breast cancer had a 15% lower
estrogens, the receptor undergoes a conformational change and 2-OH:16α-OH ratio than control subjects.8 Furthermore, those
binds to specific DNA sequences. This transcription complex with the highest 2-OH:16α-OH ratios had about a 30% lower
regulates the expression of target genes within a cell.16,17 Because risk to breast cancer than women with lower ratios.
the ER has a unique ability to bind with a wide variety of
compounds with diverse structural features, many environmental Diverse factors can add to the hormonal risk by decreasing
toxins and plant compounds can bind to the ER with varying the 2-OH:16α-OH ratio, including numerous pesticides and
affinities and modulate estrogen activity.17 carcinogens, certain drugs such as cyclosporin and cimetidine
(Tagamet), obesity, and genetic predisposition.24-27 Dietary
Two forms of the estrogen receptor, α and β, have been iden- interventions such as increased consumption of cruciferous
tified that differ in tissue distribution, binding affinity, and vegetables (e.g., broccoli and cabbage) and phytoestrogen-rich
biological function.16,17 Therefore, different target cells may foods such as soy and flaxseeds can significantly promote C-2
respond differently to the same estrogenic stimulus depending on hydroxylation and increase the 2-OH:16α-OH ratio.
the ratio of expression of the two receptor subtypes in the cell.16,17
2
Indirect Genotoxic Effects the risk of breast cancer, an effect that may be synergistically
Excessive production of reactive oxygen species has been enhanced when combined with estrogen replacement therapy.29,30
reported in breast cancer tissue, and free-radical toxicity, which Two major sources of exogenous estrogens are oral contracep-
manifests as DNA single-strand breaks, lipid peroxidation, and tives and hormone replacement therapy. Another major source is
chromosomal abnormalities, has been reported in hamsters treat- environmental toxins that are structurally similar to estrogen and
ed with estradiol.7 The oxidation of catechol estrogens (2-OH and have the ability to mimic harmful estrogens in the body.17,31 These
4-OH) yields reactive molecules called quinones. Quinones are include aromatic hydrocarbons and organochlorines found in pes-
thought to play a role in carcinogenesis by inducing DNA damage ticides, herbicides, plastics, refrigerants, and industrial solvents.
directly or as a result of redox cycling between the quinones and Furthermore, the hormones used to fatten livestock and promote
their semiquinone radicals, which generates reactive oxygen milk production may be unknowingly ingested when consuming
species including superoxide, hydrogen peroxide, and hydroxyl meat and milk products, thereby increasing one’s exposure to envi-
radicals.5,7,10 Supplementation with antioxidant nutrients can ronmental estrogens.31
reduce the oxidation of the catechols and promote greater excre-
tion of these metabolites through the methylation pathway. While these lifestyle and environmental factors do influence
the lifetime hormone burden of an individual, endogenous hor-
RISK FACTORS FOR INCREASED ESTROGEN EXPOSURE mone levels also have a genetic basis that can be an important
risk factor for hormone-dependent cancers and other conditions.
There are many lifestyle factors that can influence the body’s Family history can be an important indicator of potential prob-
production of estrogen. Obesity increases endogenous estrogen lems in this area.
production by fat tissue, where the enzyme aromatase converts
adrenal hormones into estrogen.18,28 Excess insulin in the blood- All sources of estrogens—whether environmental, dietary, or
stream prompts the ovaries to secrete excess testosterone and endogenously produced—can affect ER function (Table 1).
reduces SHBG levels, thus increasing levels of free estrogen.28 These substances can bind to estrogen α or β receptors with
Alcohol consumption increases estrogen levels, and epidemiolog- varying affinities and for varying lengths of time, producing a
ical studies suggest that moderate alcohol consumption increases wide range of estrogen-related effects.17
Dietary Estrogens32-35
Environmental Estrogens31 (“Phytoestrogens”) Endogenous Estrogens
MANIFESTATIONS OF EXCESSIVE ESTROGEN EXPOSURE tumors, fibrocystic or painful breasts, cervical dysplasia, and
AND ESTROGEN DOMINANCE systemic lupus erythematosis.
An abundance of evidence makes it clear that excessive Fortunately, beneficial modulation of estrogen metabolism
estrogen exposure from both endogenous and exogenous sources can be accomplished through dietary modification and supple-
is a causal factor in the development of cancer in hormone- mentation with select nutrients. A weight management program
dependent tissues, such as the breast, endometrium, ovary, may also be very helpful in both reducing adipose aromatase
uterus, and prostate. Furthermore, hormonal imbalances activity and facilitating more desirable estrogen metabolism and
between progesterone, testosterone, and estrogen can lead to excretion. The promotion of healthy estrogen metabolism in this
symptoms and conditions of estrogen dominance. These include way may have profound significance for diseases and conditions
premenstrual syndrome (PMS), endometriosis, uterine fibroid in which these hormones play a role.
3
NUTRITIONAL MODULATION OF Fats
ESTROGEN METABOLISM Balance among types and amounts of dietary fats may play a
role in determining balance among estrogens in the body. In male
Multiple dietary and nutritional factors have the ability to chimpanzees fed a high-fat, low-carbohydrate, low-protein diet for
influence estrogen synthesis and receptor activity, as well as the 8 weeks, estradiol was metabolized primarily through C-16α
detoxification pathways through which estrogens are metabo- hydroxylation, whereas it was metabolized primarily through C-2
lized (Table 2; Figure 1). Incorporating dietary changes with the hydroxylation in chimpanzees fed a normal diet.39 Breast cancer
use of select nutritional supplements can have profound effects in cells exposed to eicosapentaenoic acid, an omega-3 fatty acid found
beneficially influencing estrogen balance and thus preventing in cold-water fish, showed increases in C-2 hydroxylation of estra-
estrogen-related diseases and conditions. diol and decreases in C-16α hydroxylation of estradiol.24 Women
with severe premenstrual breast symptomatology who reduced
Dietary Fiber and Lignin their intake of fat while increasing their consumption of complex
carbohydrates experienced significant symptom reduction.40
Insoluble dietary fibers such as lignin (found in flaxseeds and
the bran layer of grains, beans, and seeds) can interrupt the Protein
enterohepatic circulation of estrogens in two ways, thus promot-
ing their excretion and making them less available for reabsorp- Inadequate dietary protein may lead to decreases in overall
tion and further metabolism.36 First, dietary fiber, especially cytochrome P450 activity, including cytochrome P450-1A2,
lignin, can bind unconjugated estrogens in the digestive tract, which detoxifies estradiol.41 Rice is a source of protein
which are then excreted in the feces. Second, dietary fiber can frequently used to nutritionally support hepatic detoxification
beneficially affect the composition of intestinal bacteria and function, because of its low allergy potential.42 Lysine and
reduce intestinal β-glucuronidase activity, resulting in a lowered threonine are limiting amino acids in the quality of rice protein.
deconjugation of estrogen and reduced reabsorption.37 Dietary Fortifying rice protein with lysine and threonine resulted in
fiber intake also increases serum concentrations of SHBG, thus better support of hepatic mitochondrial functions in rats fed a
reducing levels of free estradiol.38 rice protein-based diet as compared to rats fed a casein
protein-based diet or a rice protein-based diet without lysine and
Carbohydrates threonine supplementation.43
Complex carbohydrates, such as those found in vegetables Phytoestrogens
and whole grains, are preferred over simple carbohydrates for
optimizing estrogen metabolism. Excessive consumption of Phytoestrogens are plant compounds that have the capacity to
simple carbohydrates has detrimental effects by raising blood bind to ERs and appear to have both estrogenic and anti-estro-
glucose levels and stimulating insulin release, resulting in genic effects, depending on the expression of ER subtypes in tar-
secondary adverse influences on sex hormone balance. get cells and on the level of endogenous estrogen present.16,17,44
Conversely, the consumption of complex carbohydrates attenu- Phytoestrogens are currently being extensively investigated as a
ates the glycemic and insulinemic responses.28 potential alternative therapy for a range of conditions associated
Table 2. Mechanisms through which dietary and nutritional factors may influence estrogen metabolism
Mechanism of Action Nutrient
4
Figure 1.
when bound,
makes it B12 5-MTHF
unavailable COMT
to tissues) 5-FormylTHF
Endogenous Exogenous magnesium
estrogen: estrogen: Methyl-B12 THF SAM
Ovaries HRT COMT
Program to Adrenals Homocysteine TMG,
Oral contraceptives choline magnesium
improve Adipose Tissue Second hand in B6
body comp meat and dairy Cystathionine SAH
equine estrogens
β-glucuronidase to decrease 4-HYDROXYESTRONE 4-METHOXYESTRONE
Note: The proper (4-0H) (4-MeO)
type and amounts Hydroxylation Methylation
Gut (Phase I)
of macronutrients Dysbiosis (Phase II)
(protein, carbo- Antioxidants Reduce Oxidation:
hydrate, and fat) 4R Program: vitamins E, A, C, beta-carotene, mixed carotenoids,
support each step prebiotics Oxidation selenium, curcumin, N-acetylcysteine, green tea catechins
in the metabolism probiotics (polyphenols), lycopene, α-lipoic acid, flavonoids
of estrogens. fiber
Excretion
3,4 QUINONES POTENTIAL Via:
CARCINOGENIC EFFECTS -glucuronidation
flax (lignans) glutathione-S-transferase glutathione NAC -methylation
curcumin selenium -sulfation
Excretion (excretion through
GSH MERCAPTURATES urine and bile)
Acronym Key: CLA: conjugated linoleic acid, COMT: catechol-O-methyltransferase, DHEA: dehydroepiandrosterone, 5-FormylTHF: 5-formyltetrahydrofolate, HRT: hormone replacement therapy,
5-MTHF: 5-methyltetrahydrofolate, NAC: N-acetylcysteine, SAM: S-adenosylmethionine, SAH: S-adenosylhomocysteine, SHBG: sex hormone binding globulin, THF: tetrahydrofolate,
TMG: trimethylglycine ©2001, Advanced Nutrition Publications
with estrogen imbalance including menopausal symptoms, pre- have been shown to inhibit estrogen-sensitive breast cancer cell
menstrual syndrome (PMS), endometriosis, prevention of breast proliferation.59 Women consuming 10g of flaxseed per day
and prostate cancer, and protection against cardiovascular experienced longer menstrual cycle length, increased proges-
disease and osteoporosis.17,44-46 The two main classes of phyto- terone-to-estrogen ratios, and fewer anovulatory cycles, all of
estrogens are the isoflavones and lignans. which were considered to reflect improved ovarian function.60
Through their detrimental effects on intestinal flora, antibiotics
Many of the benefits of increased intakes of dietary phyto- may reduce the formation of mammalian lignans.
estrogens are due to their ability to beneficially influence estro-
gen synthesis and metabolism through a variety of mecha- Vitamin E
nisms:1.) they have a similar structure to estradiol and can bind Low serum vitamin E is associated with elevated estrogen
to the ER,16,17,45 2.) they increase plasma SHBG levels,47 3.) they levels, and women with PMS experienced symptomatic improve-
decrease aromatase activity,48 and 4.) they shift estrogen metabo- ments when given supplemental α-tocopherol.61 Vitamin E
lism away from the C-16α pathway to the C-2 pathway.49,50 inhibits in vivo and in vitro growth of breast cancer cells, possi-
bly by inhibiting the expression of vascular endothelial growth
Therefore, it may be possible to demonstrate significant hor- factor, which encourages angiogenesis.62 Furthermore, vitamin E
monal effects through dietary modification. For example, a deficiency may negatively affect cytochrome P450 function, thus
recent study found that a low-fat vegetarian diet was associated impacting estrogen detoxification.
with a 19% increase in mean serum SHBG levels, as well as
reductions in weight, body mass index, and symptoms of Magnesium
dysmenorrhea and PMS.51 Two other recent studies found that
increased isoflavone consumption decreased urinary excretion of Magnesium is an essential cofactor for the COMT enzyme,
the genotoxic estrogen metabolites 16α-OH and 4-OH, indica- and therefore optimizes the methylation and excretion of
tive of their decreased formation, and significantly increased the catechol estrogens.7 Magnesium also promotes estrogen detoxi-
2-OH:16α-OH ratio in both pre- and postmenopausal women.49,50 fication by directly increasing the activity of glucuronyl trans-
ferase, an enzyme involved in hepatic glucuronidation. Ovarian
Isoflavones—Soy is perhaps the most common food source hormones influence magnesium levels, triggering decreases at
of isoflavones, but others include legumes, alfalfa, clover, certain times during the menstrual cycle as well as altering the
licorice root, and kudzu root. Biologically active isoflavones calcium to magnesium ratio. These cyclical changes can produce
include genistein, daidzein, equol, and puerarin, and some of many of the well-known symptoms of PMS in women who are
their plant precursors include formononetin, biochanins, deficient in magnesium and/or calcium.63
genistin, and daidzin. Soy isoflavones consist primarily of
genistin and daidzin, while kudzu isoflavones consist primarily Indole-3-Carbinol (I3C)
of puerarin and daidzin. Higher intakes of soy products and I3C is a naturally occurring compound derived from crucif-
isoflavones, such as consumed in traditional Japanese diets, are erous vegetables such as broccoli, Brussels sprouts, and
associated with low rates of hormone-dependent cancers.52 The cabbage that actively promotes the breakdown of estrogen to the
average daily isoflavone intake of Japanese women is 20 to 80 beneficial metabolite, 2-OH. However, modern diets are often
mg, while that of American women is 1 to 3 mg.53 deficient in these vegetables. Fortunately, research shows that
supplementation with isolated, concentrated I3C promotes
Women given 45 mg of isoflavones daily for one month 2-hydroxlation of estrogen.64 Therefore, I3C is protective to
experienced longer menstrual cycles (increased number of days estrogen-sensitive tissues and may be beneficial to those with
between menstruation) and lower luteinizing hormone and folli- health issues related to estrogen dominance.
cle-stimulating hormone surges.54 Young women consuming 36
ounces of soymilk daily for one month also experienced longer The mechanism by which I3C promotes 2-OH formation
menstrual cycles (28.3 +/- 1.9 days before soymilk feeding, involves the selective induction of Phase 1 metabolizing
increasing to 31.8 +/- 5.1 days during the month of soymilk feed- cytochrome P450 enzymes (P450-1A1 and P450-1A2), which
ing) and lower serum estradiol levels, both effects which persist- facilitate the 2-hydroxylation of estrogen.64,65 Through this meta-
ed for two to six menstrual cycles after discontinuation of the bolic role, I3C promotes an increased ratio of 2-OH to 16α-OH
soymilk.55 In women with low levels of SHBG, consumption of a and may improve estrogen metabolism in women with poor diets
soymilk powder providing about 69 mg of isoflavones daily sub- or impaired detoxification.3,64,66 I3C may also reduce the activity
stantially increased their SHBG concentrations, an effect not of the enzyme required for the 4-hydroxylation of estrogen,
observed in women with higher initial SHBG levels.47 thereby decreasing carcinogenic 4-OH formation.67
Lignans—These compounds are found in fiber-rich foods According to a recent human study in both men and women,
and, through intestinal fermentation, are converted into supplementation with 500 mg and 400 mg of I3C, respectively,
mammalian lignans with greater biological activity, such as resulted in significantly increased urinary excretion of 2-OH,
enterolactone and enterodiol. Primary dietary sources of plant while that of nearly all other metabolites including estradiol and
lignans are flaxseed and other oil seeds, whole grains, legumes, 16α-OH was lower—indicative of their decreased formation.64 The
and vegetables.56,57 Lignans stimulate the production of SHBG in authors concluded, “These findings support the hypothesis that
the liver, and therefore reduce the levels of free estrogen in I3C-induced estrogen 2-hydroxylation results in decreased con-
circulation. Enterolactone inhibits aromatase activity, and may centration of several metabolites known to activate the estrogen
thereby decrease the conversion of testosterone and androstene- receptor. This effect may lower estrogenic stimulation in women.”
dione into estrogens in fat and breast cells.38,48,58 Lignans also
6
In a double-blind, placebo-controlled study of 57 women at (GST) and glucuronyl transferase, important in the Phase II
increased risk for breast cancer, supplementation with I3C (300- detoxification of quinones produced from the oxidation of cate-
400 mg/d for 4 weeks) proved to be a promising chemopreven- chol estrogens.78,79 Furthermore, many antioxidant nutrients and
tive agent as measured by the increased 2-OH:16α-OH ratio.68 phytonutrients can reduce the oxidation of catechol estrogen
metabolites into quinones. Notable players in this group include
Not only does I3C promote healthier estrogen metabolism, vitamins E and C, α-lipoic acid, N-acetylcysteine, the mineral
but it may also act as a “weak” or anti-estrogen. Through com- selenium, curcumin, and green tea polyphenols.
petitive inhibition, I3C has been shown to prevent the receptor
binding of “stronger,” more stimulating estrogens.69 Other mech- D-Limonene, a naturally occurring monoterpene found in the
anisms relating to I3C’s influence on tissue health involve mod- oils of citrus fruits, promotes the detoxification of estrogen by
ulating ER activity, detoxifying xenoestrogens, modulating cell inducing Phase I and Phase II enzymes in the liver, including
cycle regulation, and preventing the adhesion, migration, and GST.80 This compound has also shown great promise in the pre-
invasion of cancer cell lines.67,70,71 vention and treatment of breast and other cancers.81
7
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