| |
|
 |
ABSTRACT:
It is now well known that one of the most prominent causes of breast cancer,
as well as many other hormone related health problems in both men and
women, is excessive estrogen exposure from both endogenous and exogenous
sources. Improving estrogen metabolism can be of benefit in women with
various conditions and family histories, including a family history hi
breast, uterine, or ovarian cancer, and conditions such as endometriosis,
premenstrual syndrome, uterine fibroid tumors, fibrocystic or painful
breasts, cervical dysplasia, and systemic lupus erythematosis. Beneficial
modulation of estrogen metabolism can be accomplished through dietary
and lifestyle modifications such as increasing fiber and reducing fat,
increasing phytoestrogen intake, losing weight, and increasing exercise.
In addition, many nutrients effectively reduce estrogen load by supporting
preferred pathways of estrogen metabolism and detoxification. These include
isoflavones, indole-3-carbinol, B vitamins, magnesium, limonene, calcium
D-glucarate, and antioxidants. The influences of these nutrients on estrogen
metabolism may have profound significance for diseases and conditions
in which estrogen plays a role in clinical expression.
ESTROGEN PRODUCTION
The term "estrogen" is used to collectively describe the female
hormones, the most potent of which is estradiol. The other important-but
less powerful-estrogens are estrone and estriol. Estrogens affect the
growth, differentiation, and function of diverse target tissues throughout
the body-not just those involved in the reproductive process. Estrogens
play an important role in bone formation and maintenance, exert cardioprotective
effects, and influence behavior and mood. Estrogens also have important
actions in male tissues, such as the prostate and testes.
In women, estrogens are synthesized from cholesterol
in the ovaries in response to pituitary hormones. In an adult woman with
normal cycles, the ovarian follicle secretes 70 to 500 ug of estradiol
per day, depending on the phase of the menstrual cycle. Estradiol can
be converted to estrone and vice versa, and both can be converted to estriol,
the major urinary metabolite. Estrogens are also produced by the aromatization
of androgens in fat cells, skin, bone, and other tissues.
After menopause, most endogenous estrogen is produced
in the peripheral tissues by the conversion of androstenedione, which
is secreted by the adrenal cortex, to estrone. In addition, some estrogen
continues to be manufactured by aromatase in body fat, and the ovaries
continue to produce small amounts of the male hormone testosterone, which
is converted to estradiol. The total estrogen produced after menopause,
however, is far less than that produced during a woman's reproductive
years.
Estrogens circulate in the body bound mainly to the
sex hormone binding globulin (SHBG); however, only unbound estrogens can
enter target-tissue cells and induce biological activity. This is an important
point, because it means that any change in the concentration of SHBG will
alter estrogen metabolism by inducing changes in the availability of estrogen
to the target cell.
ESTROGEN METABOLISM AND DETOXIFICATION
Metabolism of estrogen within the body is a complex subject. Estrone and
estradiol are biochemically interconvertible and yield the same family
of estrogen metabolites as shown for estrone in Figure I. Because these
metabolites vary greatly in biological activity, the ultimate biologic
effect of estrogen depends on how it is metabolized. The metabolism of
estrogen takes place primarily in the liver through Phase I (hydroxylation)
and Phase II (methylation, glucuronidation, and sulfation) pathways, with
final excretion in the urine and feces.
* Hydroxylation
Cytochrome P-450 enzymes mediate the hydroxylation of estraliol and estrone,
which is the major Phase I metabolic pathway for endogenous estrogens.
This takes place at two primary sites on the estrogen molecule, either
at the 2 carbon (C-2) position yielding 2-hydroxyestrone (2-0H) or at
the 16a carbon (C-16a) position yielding 16a-OH. A minor contribution
is made from hydroxylation at the 4 carbon (C-4) position yielding 4-0H.
The 2-0H metabolite confers very weak estrogenic activity, and is generally
termed the "good" estrogen. In contrast, the 16a-OH and 4-0H
metabolites show persistent estrogenic activity and promote tissue proliferation.
It is suggested that women who metabolize a larger proportion of their
endogenous estrogen via the C-16a hydroxylation pathway may be at significantly
elevated risk of breast cancer compared with women who metabolize proportionally
more estrogen via the C-2 pathway. Furthermore, it is theorized that shifting
estrogen balance toward a less estrogenic state through promotion of the
C-2 pathway may prove beneficial for a variety of conditions related to
estrogen dominance or imbalance.
* Methylation
The 2-0H and 4-0H metabolites (catechol estrogens) are readily oxidized
to quinones, which are highly reactive and can damage DNA and promote
carcinogenesis directly or indirectly through the generation of reactive
oxygen species (ROS). This harmful pathway can be minimized through detoxification
and excretion of the catechol estrogens via Phase II methylation by the
catechol-O-methyltransferase (COMT) enzymes. This methylation requires
S-adenosylmethionine (SAM) and I magnesium as cofactors. COMT is present
in most tissues and converts catechols into their corresponding methyl
ester metabolites, which are more water solubles. Recent data suggest
that the methylation of 4-0H renders this harmful I metabolite significantly
less active, while 2-methoxyestrone may manifest beneficial properties
by inhibiting breast cancer. Therefore, supporting the methylation pathways
promotes detoxification of estrogens and provides for more beneficial
metabolites of estrogen.
* Glucuronidation
Glucuronidation is one of the key Phase II liver detoxification pathways
for estrogens and other toxins. Glucuronic acid is conjugated with the
estrogen to facilitate its elimination from the body. Unfortunately, some
intestinal bacteria (mostly pathogenic) possess an enzyme, glucuronidase,
that uncouples the bond between excreted estrogen and glucuronic acid
in the large intestine, allowing the estrogen to reenter circulation (enterohepatic
recirculation). Not surprising is the finding that excess glucuronidase
activity is associated with an increased cancer risk, including breast
cancer. The activity of glucuronidase is increased when the diet is high
in fat and low in fiber, and can be reduced by establishing a proper bacterial
flora by eating a diet high in plant foods and supplementing the diet
with the "friendly bacteria" Lactobacillus acidophilus and Bifidobacterium
infantis.
ESTROGEN RECEPTORS
Estrogens, like all steroid hormones, have a wide range of actions and
affect almost all systems in the body, yet act in a tissue-specific manner.
Estrogens act by binding with high affinity to the estrogen receptor (ER)
in target cells. Once bound by estrogens, the receptor activates the transcription
of estrogen-responsive target genes. Because the ER has a unique ability
to bind with a wide variety of compounds with diverse structural features,
many environmental toxins and plant compounds can bind to the ER with
varying affinities and modulate estrogen activity.
Two forms of the estrogen receptor, a and b, have been
identified that differ in tissue distribution, binding affinity, and biological
function. Therefore, different target cells may respond differently to
the same estrogenic stimulus depending on the ratio of expression of the
two receptor subtypes in the cell. This helps to explain how phytoestrogens
and the new designer estrogen drugs such as tamoxifen and raloxifene-called
selective estrogen receptor modulators (SERMs )-behave like estrogens
in some tissues but block its action in others. Unraveling the detailed
physiological role of each receptor subtype is needed to further elucidate
the complex nature of estrogen's mechanisms of action.
ESTROGEN AND CANCER RISK
Epidemiological and animal studies have identified estrogen exposure as
a risk factor for several cancers, namely breast, endometrium, ovary,
prostate, testis, and thyroid. Much of the evidence comes from the observation
that cancer risk increases with increased exposure to endogenous or exogenous
estrogens, and the positive relationship observed between blood levels
of estrogens and cancer risk. Prolonged estrogen exposure can cause direct
genotoxic effects by inducing cell proliferation in estrogen-dependent
target cells (increasing the opportunity for the accumulation of random
genetic errors), affecting cellular differentiation, and altering gene
expression. Additionally, there is increasing evidence for indirect genotoxic
effects of estrogens as well. The relative importance of each mechanism
is likely a function of the specific estrogen, as well as the exposed
tissue or cell type and its metabolic state.
Direct Genotoxic Effects
Evidence is accumulating that some estrogen metabolites may be directly
responsible for the initial genetic damage leading to tumors. 16a-OH and
4-0H are the primary estrogen metabolites that have been associated with
direct genotoxic effects and carcinogenicity. Some researchers believe
increased levels of 16a-OH may increase the risk of breast cancer by increasing
both cell proliferation and direct DNA damage; however, scientific consensus
has not yet been reached. Conversely, 2-0H may induce apoptosis and thereby
inhibit cell proliferation, an important mechanism in the prevention of
cancer.
A recent 5-year prospective study of 10, 786 women was
conducted to investigate the role of estrogen metabolism as a predictor
of breast cancer, specifically the ratio of 2-0H to 16a-OH. The researchers
found that premenopausal women who developed breast cancer had a decreased
2-0H:16a-OH ratio and a higher percentage of 16a-OH than 2-0H. Women with
predominately 2-0H were 40% less likely to have developed breast cancer
during the 5 years. Another recent case control study that began in 1977
found that postmenopausal women who developed breast cancer had a 15%
lower 2-0H:16a-OH ratio than control subjects. Furthermore, those with
the highest 2-0H:16a-OH ratios had about a 30% lower risk to breast cancer
than women with lower ratios.
Diverse factors can add to the hormonal risk by decreasing
the 2-0H: 16a-OH ratio, including numerous pesticides and carcinogens,
certain drugs such as cyclosporin and cimetidine (Tagamet), obesity, and
genetic predisposition. Dietary interventions such as increased consumption
of cruciferous vegetables (e.g., broccoli and cabbage) and phytoestrogen-rich
foods such as soy and flaxseeds can significantly promote C-2 hydroxylation
and increase the 2-0H:16a-OH ratio.
Indirect Genotoxic Effects
Excessive production of ROS has been reported in breast cancer tissue,
and free-radical toxicity, which manifests as DNA single- strand breaks,
lipid peroxidation, and chromosomal abnormalities, has been reported in
hamsters treated with estradiol. The oxidation of catechol estrogens (2-0H
and 4-0H) yields reactive molecules called quinones. Quinones are thought
to playa role in carcinogenesis by inducing DNA damage directly or as
a result of redox cycling between the quinones and their semi-quinone
radicals, which generates ROS. Supplementation with antioxidant nutrients
can reduce the oxidation of the catechols and promote greater excretion
of these metabolites through the methylation pathway.
RISK FACTORS FOR INCREASED ESTROGEN
EXPOSURE
There are many lifestyle factors that can influence the body's production
of estrogen. Obesity increases endogenous estrogen I production by fat
tissue, where the enzyme aromatase converts I androgens into estrogen.
Excess insulin in the bloodstream prompts the ovaries to secrete excess
testosterone and reduces SHBG levels, thus increasing levels of free estrogen.
Alcohol consumption increases estrogen levels, and epidemiological studies
suggest that moderate alcohol consumption increases the risk of breast
cancer, an effect that may be synergistically enhanced when combined with
estrogen replacement therapy.
MANIFESTATIONS OF EXCESSIVE ESTROGEN
EXPOSURE AND ESTROGEN DOMINANCE
An abundance of evidence makes it clear that excessive estrogen exposure
from both endogenous and exogenous sources is a causal factor in the development
of cancer in hormone-dependent tissues, such as the breast, endometrium,
ovary, uterus, and prostate.
Furthermore, hormonal imbalances between progesterone,
testosterone, and estrogen can lead to symptoms and conditions of estrogen
dominance. These include premenstrual syndrome (PMS), endometriosis, uterine
fibroid tumors, fibrocystic or painful breasts, cervical dysplasia, and
systemic lupus erythematosis.
NUTRITIONAL MODULATION OF ESTROGEN
METABOLISM
Multiple dietary and nutritional factors have the ability to influence
estrogen synthesis and receptor activity, as well as the detoxification
pathways through which estrogens are metabolized. Incorporating dietary
changes with the use of select nutritional supplements can have profound
effects in beneficially influencing estrogen balance and thus preventing
estrogen-related.
Two major sources of exogenous estrogens are oral contraceptives
and hormone replacement therapy. Another major source is environmental
toxins found in pesticides, herbicides, plastics, refrigerants, and industrial
solvents that are structurally similar to estrogen and have the ability
to mimic harmful estrogens in the body. Furthermore, the hormones used
to fatten livestock and promote milk production are found in meat and
milk products, thereby increasing one's exposure to environmental estrogens.
While these lifestyle and environmental factors do influence
the lifetime hormone burden of an individual, endogenous hormone levels
also have agenetic basis that can be an important risk factor for hormone-dependent
cancers and other conditions. Thus, family history can be a valuable indicator
of potential problems in this area. All sources of estrogens-whether environmental,
dietary, or endogenously produced--can affect ER function. These substances
can bind to estrogen a or b receptors with varying affinities and for
varying lengths of time, producing a wide range of estrogen-related effects
diseases and conditions. A weight management program may also be very
helpful in both reducing adipose aromatase activity and facilitating more
desirable estrogen metabolism and excretion.
Dietary Fiber and Lignin
Insoluble dietary fibers such as lignin (found in flaxseeds and the bran
layer of grains, beans, and seeds) can interrupt the enterohepatic circulation
of estrogens in two ways, thus promoting their excretion and making them
less available for reabsorption and further metabolism.36 First, dietary
fiber, especially lignin, can bind unconjugated estrogens in the digestive
tract, which are then excreted in the feces. Second, dietary fiber can
beneficially affect the composition of intestinal bacteria and reduce
intestinal b-glucuronidase activity, resulting in a lowered the conjugation
of estrogen and reduced reabsorption. Dietary fiber intake also increases
serum concentrations of SHBG, thus reducing levels of free estradiol.
Carbohydrates/Fats/Protein
Complex carbohydrates, such as those found in vegetables and whole grains,
are preferred over simple carbohydrates for optimizing estrogen metabolism.
Excess consumption of simple carbohydrates raises blood glucose and insulin
levels, resulting in adverse influences on sex hormone balance. Conversely,
complex carbohydrates attenuate glycemic and insulinemic responses.
The types and amounts of dietary fats may play a role
in determining balance among estrogens in the body. For instance, high-fat
diets may promote C-16a hydroxylation over C-2 hydroxylation. Furthermore,
omega-3 fatty acids such as eicosapentaenoic acid (EPA) have been shown
to increase C-2 hydroxylation and decrease C-16a hydroxylation of estradiol
in breast cancer cells.
Inadequate dietary protein may lead to decreases in
overall cytochrome P450 activity, including cytochrome P450-IA2, which
detoxifies estradiol. Rice fortified with lysine and threonine is a source
of protein frequently used to nutritionally support hepatic detoxification
function, because of its low allergy potential. Soy is also an excellent
source of protein that is low in fat and provides the health benefits
of isoflavones.
Phytoestrogens
Phytoestrogens are plant compounds that have the capacity to bind to ERs
and appear to have both estrogenic and anti-estrogenic effects, depending
on the expression of ER subtypes in target cells and on the level of endogenous
estrogen present. They are currently being extensively investigated as
a potential alternative therapy for a range of conditions associated with
estrogen imbalance including menopausal symptoms, PMS, and endometriosis,
as well as prevention of breast and prostate cancer and protection against
cardiovascular disease and osteoporosis. The two main classes of phytoestrogens
are the isoflavones and lignans. Phytoestrogens beneficially influence
estrogen synthesis and metabolism through a variety of mechanisms: 1)
they have a similar structure to estradiol and can bind to the ER, 2.)
they increase plasma SHBG levels, 3.) they decrease aromatase activity,46
and 4.) they shift estrogen metabolism away from the C-16a pathway to
the C-2 pathway.
Therefore, it may be possible to demonstrate significant
hormonal effects through dietary modification. For example, two recent
studies found that increased isoflavone consumption increased urinary
excretion of the genotoxic estrogens l6a-OH and 4-0H, indicative of their
decreased formation, significantly increased the 2-0H:16a-OH ratio in
both pre postmenopausal women.
Isoflavones- Soy is perhaps the most common food source
of isoflavones, but others include legumes, alfalfa, clover, licorice,
and kudzu root. There are several biologically active llavones, such as
genistein, daidzein, and puerarin, with each Ilt source delivering a different
profile. Higher intakes of soy ducts and isoflavones, such as consumed
in traditional Japanese diets, are associated with low rates of hormone
dependent can. The average daily isoflavone intake of Japanese women is
20 mg, while that of American women is 1 to 3 mg.
In two human studies, women given isoflavone supplements
and milk for one month experienced longer menstrual cycles and serum estradiol
levels.51.52 Longer menstrual cycles are beneficial because they result
in decreased lifetime exposure to estrogen and lower the risk for breast
cancer. Furthermore, in men with low levels of SHBG, consumption of a
soymilk powder providing about 69 mg of isoflavones daily substantially
increased their SHBG concentrations, an effect not observed in men with
higher initial SHBG levels.
Lignans- These compounds are found in fiber-rich foods
such flaxseed and other oil seeds, whole grains, legumes, and vegetables.
Lignans stimulate the production of SHBG in the liver, and therefore reduce
the levels of free estrogen insulation. They also inhibit aromatase activity,
thus decreasing conversion of testosterone and androstenedione into estrogens
in fat and breast cells. Lignans also have been shown to inhibit estrogen-sensitive
breast cancer cell proliferation. Women consuming 10g of flaxseed per
day experienced longer menstrual cycle length, increased progesterone-to-estrogen
ratios, and fewer anovulatory cycles, all of which were considered to
reflect improved ovarian function.
Resveratrol- This bioflavonoid occurs naturally in grapes
and red wine and has been shown to inhibit breast cancer cell growth in
vitro. It has been classified as a phytoestrogen based on its ability
to bind to and activate the ER, with recent in vitro studies indicating
that it exhibits estrogenic and anti-estrogenic activity and binds to
ERa and ERb with comparable affinity. These estrogen modulatory effects
may explain resveratrol's well- known anticancer and cardioprotective
properties.
Vitamin E
Low serum vitamin E is associated with elevated estrogen levels, and supplementation
may reduce symptoms of PMS. Vitamin E inhibits growth of breast cancer
cells, possibly by inhibiting the expression of vascular endothelial growth
factor, which encourages angiogenesis.63 Furthermore, vitamin E deficiency
may negatively affect cytochrome P450 function, thus impacting estrogen
detoxification.
Magnesium
Magnesium is an essential cofactor for the COMT enzyme, and therefore
optimizes the methylation and excretion of catechol estrogens. Magnesium
also promotes estrogen detoxification by directly increasing the activity
of glucuronyl transferase, an enzyme involved in hepatic glucuronidation.
Ovarian hormones influence magnesium levels, triggering decreases at certain
times during the menstrual cycle as well as altering the calcium to magnesium
ratio. These cyclical changes can produce many of the well-known symptoms
of PMS in women who are deficient in magnesium and/or calcium.
Indole-3-Carbinol (l3C)
I3C is a naturally occurring compound derived from cruciferous vegetables
such as broccoli, Brussels sprouts, and cabbage that actively promotes
the breakdown of estrogen to the beneficial metabolite, 2-OH. Therefore,
I3C is protective to estrogen-sensitive tissues and may be beneficial
to those with health issues related to estrogen dominance.
The mechanism by which I3C promotes 2-OH formation involves
the selective induction of Phase 1 metabolizing cytochrome P450 enzymes,
which facilitate the 2-hydroxylation of estrogen. Through this metabolic
role, I3C promotes an increased ratio of 2-OH to l6a-OH and may improve
estrogen metabolism in women with poor diets or impaired detoxification.
I3C may also reduce the activity of the enzyme required for the 4-hydroxylation
of estrogen, thereby decreasing carcinogenic 4-OH formation.
According to a recent human study in both men and women,
supplementation with 500 mg and 400 mg of I3C, respectively, resulted
in significantly increased urinary excretion of 2-OH, while that of nearly
all other metabolites including estradiol and l6a-OH was lower-indicative
of their decreased formation. In another double-blind, placebo-controlled
study of 57 women at increased risk for breast cancer, supplementation
with I3C (300-400 mg/d for 4 weeks) proved to be a promising chemopreventive
agent as measured by the increased 2-OH: l6a- OH ratio.
Not only does I3C promote healthier estrogen metabolism,
but it may also act as a "weak," or anti-estrogen. Through competitive
inhibition, 13C has been shown to prevent the receptor binding of "stronger,"
more stimulating estrogens!" Other mechanisms relating to I3C's influence
on tissue health involve modulating ER activity, detoxifying xenoestrogens,
modulating cell cycle regulation, and preventing the adhesion, migration,
and invasion of cancer cell lines.
B Vitamins
The B vitamins, such as B6, B12 and folate, function as important cofactors
for enzymes involved in estrogen conjugation and methylation. Therefore,
decreased levels of B vitamins can disrupt estrogen detoxification and
lead to increased levels of circulating estrogens. For instance, folate
(as a precursor to SAM) is an essential cofactor for the methylation of
catechol estrogens, 2-OH and 4-OH, which reduces their conversion to the
carcinogenic quinones. Unfortunately, many individuals have agenetic polymorphism
that interferes with their ability to metabolize folic acid to the active
form utilized by the body. Supplementing with a metabolically active form
of folate that doesn't require enzymatic conversion, such as L-5-methyl
tetrahydrofolate, will ensure that these patients maintain adequate folate
nutriture.
Another way in which certain B vitamins playa role in
estrogen activity is through a potential to modulate the cell's response
to activation of the ER. It has been demonstrated that elevated intra-cellular
concentrations of the active form of vitamin B6 can lead to significantly
decreased gene transcription responses when estrogen binds to the ER By
modulating estrogen-induced gene expression in this way, vitamin B6 can
attenuate the biological effects of estrogen. B vitamins also playa role
in the prevention of cancer because they are crucial for DNA synthesis
and repair as well as the process of DNA methylation, which is essential
for DNA stability and integrity and is an important regulator of gene
expression.
Calcium D-Glucarate
Calcium D-glucarate is a natural compound that appears to have some influence
on breast cancer by aiding in detoxification and the regulation of estrogen.
It not only inhibits b-glucuronidase, but also increases the activity
of the glucuronidation Phase II pathway, with the net effect of increased
estrogen and toxin elimination from the body. Calcium D-glucarate has
been found in animal models to lower estradiol levels and inhibit the
initiation, promotion, and progression of cancer.
Other Beneficial Phytonutrients
There are many other naturally occurring compounds derived from a variety
of plant sources that promote healthy estrogen metabolism. Curcumin is
a polyphenol complex from the curry spice turmeric, a member of the ginger
family. A combination of curcumin and the isoflavone genistein has shown
synergy in reducing xenoestrogen-induced growth of breast cancer cells.
Curcumin also increases hepatic levels of glutathione and induces glutathione-S-transferase
(GST) and glucuronyl transferase, important in the Phase II detoxification
of quinones produced from the oxidation of catechol estrogens. Chrysin
is a bioflavonoid that has been shown to inhibit aromatase activity, thus
reducing the conversion of androgens into estrogen. Aromatase is found
in breast tissue, and its inhibition may be useful in reducing the cell
proliferative effects of estrogen. Preliminary research indicates that
the herb rosemary promotes the 2-hydroxylation of estrogen in a similar
fashion to 13C, and may inhibit 16a hydroxylation. Rosemary may also enhance
estrogen detoxification.
Furthermore, many antioxidants and phytonutrients can
reduce the oxidation of catechol estrogen metabolites into quinones. Notable
players in this group include vitamins E and C, a-lipoic acid, N-acetylcysteine,
the mineral selenium, curcumin, and green tea. D-Limonene, a naturally
occurring monoterpene found in the oils of citrus fruits, promotes the
detoxification of estrogen by inducing Phase I and Phase II enzymes in
the liver, including GST. This compound has also shown great promise in
the prevention and treatment of breast and other cancers.
There are also many hormone-modulating herbs that have
along history of traditional use in treating women 's health conditions,
including black cohosh, chasteberry, ginseng, dong quai, and licorice.
While the mechanism of action of these herbs varies, many have been found
to contain phytoestrogens. For a comprehensive discussion of the use of
nutritional supplements and herbs in treating PMS, menopause, and other
women's health conditions, please refer to the articles titled, Premenstrual
Syndrome: A Natural Approach to Management; A Healthy Menstrual Cycle;
A Natural Approach to Menopause; and Black Cohosh and Chastebeny: Herbs
Valued by Women for Centuries.
For a copy of this transcript,
please contact us.
|
