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MET451 1/01 APPLIED NUTRITIONAL SCIENCE REPORTSCopyright 2001 by Advanced Nutrition Publications, Inc.
Nutritional Influences on Estrogen Metabolism
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. These include isoflavones, indole-3-carbinol, family history of breast, uterine, or ovarian cancer, and condi- B vitamins, magnesium, limonene, calcium D-glucarate, and tions such as endometriosis, premenstrual syndrome, uterine antioxidants. The influences of these nutrients on estrogen fibroid tumors, fibrocystic or painful breasts, cervical dysplasia, metabolism may have profound significance for diseases and and systemic lupus erythematosis. Beneficial modulation of conditions in which estrogen plays a role in clinical expression. ESTROGEN PRODUCTION
important point, because it means that any change in the concen-tration of SHBG will alter estrogen metabolism by inducing The term “estrogen” is used to collectively describe the female changes in the availability of estrogen to the target cell. hormones, the most potent of which is estradiol. The otherimportant—but less powerful—estrogens are estrone and estri- ESTROGEN METABOLISM AND DETOXIFICATION
ol. Estrogens affect the growth, differentiation, and function ofdiverse target tissues throughout the body—not just those Metabolism of estrogen within the body is a complex subject involved in the reproductive process. Estrogens play an impor- (Figure 1). Estrone and estradiol are biochemically interconvert- tant role in bone formation and maintenance, exert cardiopro- ible and yield the same family of estrogen metabolites as shown tective effects, and influence behavior and mood. Estrogens for estrone in Figure 1. Because these metabolites vary greatly in also have important actions in male tissues, such as the prostate biological activity, the ultimate biologic effect of estrogen depends on how it is metabolized. The metabolism of estrogentakes place primarily in the liver through Phase I (hydroxylation) In women, estrogens are synthesized from cholesterol in the and Phase II (methylation, glucuronidation, and sulfation) path- ovaries in response to pituitary hormones. In an adult woman ways, with final excretion in the urine and feces.1 with normal cycles, the ovarian follicle secretes 70 to 500 µg ofestradiol per day, depending on the phase of the menstrual cycle.
Estradiol can be converted to estrone and vice versa, and both Cytochrome P-450 enzymes mediate the hydroxylation of estra- can be converted to estriol, the major urinary metabolite.
diol and estrone, which is the major Phase I metabolic Estrogens are also produced by the aromatization of androgens in pathway for endogenous estrogens. This takes place at two fat cells, skin, bone, and other tissues.
primary sites on the estrogen molecule, either at the 2 carbon(C-2) position yielding 2-hydroxyestrone (2-OH) or at the After menopause, most endogenous estrogen is produced in the 16α carbon (C-16α) position yielding 16α-OH. A minor contri- peripheral tissues by the conversion of androstenedione, which is bution is made from hydroxylation at the 4 carbon (C-4) position secreted by the adrenal cortex, to estrone. In addition, some yielding 4-OH.3 The 2-OH metabolite confers very weak estro- estrogen continues to be manufactured by aromatase in body fat, genic activity, and is generally termed the “good” estrogen. In and the ovaries continue to produce small amounts of the male contrast, the 16α-OH and 4-OH metabolites show persistent hormone testosterone, which is converted to estradiol. The total estrogenic activity and promote tissue proliferation.3-6 It is estrogen produced after menopause, however, is far less than that suggested that women who metabolize a larger proportion of produced during a woman’s reproductive years.1,2 their endogenous estrogen via the C-16α hydroxylation pathwaymay be at significantly elevated risk of breast cancer compared Estrogens circulate in the body bound mainly to the sex hormone with women who metabolize proportionally more estrogen via binding globulin (SHBG); however, only unbound estrogens can the C-2 pathway.3-5,7-9 Furthermore, it is theorized that shifting enter target-tissue cells and induce biological activity.1,2 This is an estrogen balance toward a less estrogenic state through promo- tion of the C-2 pathway may prove beneficial for a variety of subtype is needed to further elucidate the complex nature of conditions related to estrogen dominance or imbalance.
The 2-OH and 4-OH metabolites (catechol estrogens) are read-ily oxidized to quinones, which are highly reactive and can dam- Epidemiological and animal studies have identified estrogen age DNA and promote carcinogenesis directly or indirectly exposure as a risk factor for several cancers, namely breast,endometrium, ovary, prostate, testis, and thyroid. Much of the through the generation of reactive oxygen species (ROS). This evidence comes from the observation that cancer risk increases harmful pathway can be minimized through detoxification and with increased exposure to endogenous or exogenous estrogens, excretion of the catechol estrogens via Phase II methylation by and the positive relationship observed between blood levels of the catechol-O-methyltransferase (COMT) enzyme.5,10,11 This estrogens and cancer risk.7,18-22 Prolonged estrogen exposure can methylation requires S-adenosylmethionine (SAM) and cause direct genotoxic effects by inducing cell proliferation in magnesium as cofactors.11 COMT is present in most tissues and estrogen-dependent target cells (increasing the opportunity for converts catechols into their corresponding methyl ester the accumulation of random genetic errors), affecting cellular metabolites, which are more water soluble.5,7 Recent data differentiation, and altering gene expression. Additionally, there suggest that the methylation of 4-OH renders this harmful is increasing evidence for indirect genotoxic effects of estrogens metabolite significantly less active, while 2-methoxyestrone as well. The relative importance of each mechanism is likely a may manifest beneficial properties by inhibiting breast function of the specific estrogen, as well as the exposed tissue or cancer.10,12 Therefore, supporting the methylation pathways promotes detoxification of estrogens and provides for morebeneficial metabolites of estrogen. Direct Genotoxic Effects
Evidence is accumulating that some estrogen metabolites may bedirectly responsible for the initial genetic damage leading to Glucuronidation is one of the key Phase II liver detoxification tumors. 16α-OH and 4-OH are the primary estrogen metabolites pathways for estrogens and other toxins. Glucuronic acid is that have been associated with direct genotoxic effects and conjugated with the estrogen to facilitate its elimination from the carcinogenicity.5,7 Some researchers believe increased levels of body.1 Unfortunately, some intestinal bacteria (mostly pathogen- 16α-OH may increase the risk of breast cancer by increasing both ic) possess an enzyme, β-glucuronidase, that uncouples the bond cell proliferation and direct DNA damage; however, scientific between excreted estrogen and glucuronic acid in the large intes- consensus has not yet been reached.5,7-9,23 Conversely, 2-OH may tine, allowing the estrogen to reenter circulation (enterohepatic induce apoptosis and thereby inhibit cell proliferation, an impor- recirculation).13 Not surprising is the finding that excess tant mechanism in the prevention of cancer.12 β-glucuronidase activity is associated with an increased cancerrisk, including breast cancer.14 The activity of β-glucuronidase A recent 5-year prospective study of 10,786 women was is increased when the diet is high in fat and low in fiber, and conducted to investigate the role of estrogen metabolism as a can be reduced by establishing a proper bacterial flora by predictor of breast cancer, specifically the ratio of 2-OH to eating a diet high in plant foods and supplementing the 16α-OH.4 The researchers found that premenopausal women diet with the “friendly bacteria” Lactobacillus acidophilus and who developed breast cancer had a decreased 2-OH:16α-OH ratio and a higher percentage of 16α-OH than 2-OH. Womenwith predominately 2-OH were 40% less likely to have devel- ESTROGEN RECEPTORS
oped breast cancer during the 5 years. Another recent case-control study that began in 1977 found that postmenopausal Estrogens, like all steroid hormones, have a wide range of actions women who developed breast cancer had a 15% lower and affect almost all systems in the body, yet act in a tissue- 2-OH:16α-OH ratio than control subjects.8 Furthermore, those specific manner. Estrogens act by binding with high affinity to the with the highest 2-OH:16α-OH ratios had about a 30% lower estrogen receptor (ER) in target cells. Once bound by estrogens, risk to breast cancer than women with lower ratios.
the receptor activates the transcription of estrogen-responsive tar-get genes.16,17 Because the ER has a unique ability to bind with a Diverse factors can add to the hormonal risk by decreasing the wide variety of compounds with diverse structural features, many 2-OH:16α-OH ratio, including numerous pesticides and environmental toxins and plant compounds can bind to the ER carcinogens, certain drugs such as cyclosporin and cimetidine with varying affinities and modulate estrogen activity.17 (Tagamet), obesity, and genetic predisposition.24-27 Dietaryinterventions such as increased consumption of cruciferous Two forms of the estrogen receptor, α and β, have been identi- vegetables (e.g., broccoli and cabbage) and phytoestrogen-rich fied that differ in tissue distribution, binding affinity, and foods such as soy and flaxseeds can significantly promote C-2 biological function.16,17 Therefore, different target cells may hydroxylation and increase the 2-OH:16α-OH ratio.
respond differently to the same estrogenic stimulus depending onthe ratio of expression of the two receptor subtypes in the cell.16,17 Indirect Genotoxic Effects
This helps to explain how phytoestrogens and the new designer Excessive production of ROS has been reported in breast cancer estrogen drugs such as tamoxifen and raloxifene—called tissue, and free-radical toxicity, which manifests as DNA single- selective estrogen receptor modulators (SERMs)—behave like strand breaks, lipid peroxidation, and chromosomal abnormali- estrogens in some tissues but block its action in others.
ties, has been reported in hamsters treated with estradiol.7 The Unraveling the detailed physiological role of each receptor oxidation of catechol estrogens (2-OH and 4-OH) yields reactive molecules called quinones. Quinones are thought to play a role Two major sources of exogenous estrogens are oral contracep- in carcinogenesis by inducing DNA damage directly or as a tives and hormone replacement therapy. Another major source is result of redox cycling between the quinones and their semi- environmental toxins found in pesticides, herbicides, plastics, quinone radicals, which generates ROS.5,7,10 Supplementation refrigerants, and industrial solvents that are structurally similar with antioxidant nutrients can reduce the oxidation of the cate- to estrogen and have the ability to mimic harmful estrogens in chols and promote greater excretion of these metabolites through the body.17,31 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 RISK FACTORS FOR INCREASED ESTROGEN EXPOSURE
There are many lifestyle factors that can influence the body’s While these lifestyle and environmental factors do influence theproduction of estrogen. Obesity increases endogenous estrogen lifetime hormone burden of an individual, endogenous hormone production by fat tissue, where the enzyme aromatase converts levels also have a genetic basis that can be an important risk fac- androgens into estrogen.18,28 Excess insulin in the bloodstream tor for hormone-dependent cancers and other conditions. Thus, prompts the ovaries to secrete excess testosterone and reduces family history can be a valuable indicator of potential problems SHBG levels, thus increasing levels of free estrogen.28 Alcohol in this area. All sources of estrogens—whether environmental, consumption increases estrogen levels, and epidemiological stud- dietary, or endogenously produced—can affect ER function ies suggest that moderate alcohol consumption increases the risk (Table 1). These substances can bind to estrogen α or β receptors of breast cancer, an effect that may be synergistically enhanced with varying affinities and for varying lengths of time, produc- when combined with estrogen replacement therapy.29,30 ing a wide range of estrogen-related effects.17 Table 1. Sources of Estrogens
Environmental Estrogens31
Dietary Estrogens32-35 (“Phytoestrogens”)
Endogenous Estrogens
• Organochlorine chemicals such as vinyl • Isoflavones (e.g., genistein, daidzein, perchloroethylene (~half of “endocrine biochanins) from soy, beans, peas, clover, • Aromatic hydrocarbons, phthalates and • Lignans (e.g., matairesinol, pinoresinol, secoisolariciresinol) especially fromflaxseed, rye, wheat, and sea vegetables • Certain flavonoids (e.g., rutin, naringenin, luteolin, resveratrol, quercetin) especially MANIFESTATIONS OF EXCESSIVE ESTROGEN EXPOSURE
diseases and conditions. A weight management program may also AND ESTROGEN DOMINANCE
be very helpful in both reducing adipose aromatase activity andfacilitating more desirable estrogen metabolism and excretion.
An abundance of evidence makes it clear that excessive estrogenexposure from both endogenous and exogenous sources is a causal Dietary Fiber and Lignin
factor in the development of cancer in hormone-dependent tissues,such as the breast, endometrium, ovary, uterus, and prostate.
Insoluble dietary fibers such as lignin (found in flaxseeds and Furthermore, hormonal imbalances between progesterone, testos- the bran layer of grains, beans, and seeds) can interrupt the terone, and estrogen can lead to symptoms and conditions of estro- enterohepatic circulation of estrogens in two ways, thus promot- gen dominance. These include premenstrual syndrome (PMS), ing their excretion and making them less available for reabsorp- endometriosis, uterine fibroid tumors, fibrocystic or painful tion and further metabolism.36 First, dietary fiber, especially breasts, cervical dysplasia, and systemic lupus erythematosis. lignin, can bind unconjugated estrogens in the digestive tract,which are then excreted in the feces. Second, dietary fiber can NUTRITIONAL MODULATION OF
beneficially affect the composition of intestinal bacteria and ESTROGEN METABOLISM
reduce intestinal β-glucuronidase activity, resulting in a lowereddeconjugation of estrogen and reduced reabsorption.37 Dietary Multiple dietary and nutritional factors have the ability to influence fiber intake also increases serum concentrations of SHBG, thus estrogen synthesis and receptor activity, as well as the detoxifica- tion pathways through which estrogens are metabolized (Table 2;Figure 1). Incorporating dietary changes with the use of select Carbohydrates/Fats/Protein
nutritional supplements can have profound effects in beneficially Complex carbohydrates, such as those found in vegetables and influencing estrogen balance and thus preventing estrogen-related whole grains, are preferred over simple carbohydrates for optimizing estrogen metabolism. Excess consumption of simple Therefore, it may be possible to demonstrate significant hor- carbohydrates raises blood glucose and insulin levels, resulting in monal effects through dietary modification. For example, two adverse influences on sex hormone balance. Conversely, complex recent studies found that increased isoflavone consumption carbohydrates attenuate glycemic and insulinemic responses.28 decreased urinary excretion of the genotoxic estrogen metabo-lites 16α-OH and 4-OH, indicative of their decreased formation, The types and amounts of dietary fats may play a role in deter- and significantly increased the 2-OH:16α-OH ratio in both pre- mining balance among estrogens in the body. For instance, high- fat diets may promote C-16α hydroxylation over C-2 hydroxyla-tion.39 Furthermore, omega-3 fatty acids such as eicosapentaenoic Isoflavones—Soy is perhaps the most common food source of
acid (EPA) have been shown to increase C-2 hydroxylation and isoflavones, but others include legumes, alfalfa, clover, licorice decrease C-16α hydroxylation of estradiol in breast cancer cells.24 root, and kudzu root. There are several biologically activeisoflavones, such as genistein, daidzein, and puerarin, with each Inadequate dietary protein may lead to decreases in overall plant source delivering a different profile. Higher intakes of soy cytochrome P450 activity, including cytochrome P450-1A2, products and isoflavones, such as consumed in traditional Japanese which detoxifies estradiol.40 Rice fortified with lysine and thre- diets, are associated with low rates of hormone-dependent can- onine is a source of protein frequently used to nutritionally sup- cers.49 The average daily isoflavone intake of Japanese women is 20 port hepatic detoxification function, because of its low allergy to 80 mg, while that of American women is 1 to 3 mg.50 potential.41 Soy is also an excellent source of protein that is lowin fat and provides the health benefits of isoflavones.
In two human studies, women given isoflavone supplements andsoymilk for one month experienced longer menstrual cycles and Phytoestrogens
lower serum estradiol levels.51,52 Longer menstrual cycles are Phytoestrogens are plant compounds that have the capacity to beneficial because they result in decreased lifetime exposure to bind to ERs and appear to have both estrogenic and anti-estro- estrogen and lower the risk for breast cancer. Furthermore, in genic effects, depending on the expression of ER subtypes in tar- women with low levels of SHBG, consumption of a soymilk pow- get cells and on the level of endogenous estrogen present.16,17,42 der providing about 69 mg of isoflavones daily substantially They are currently being extensively investigated as a potential increased their SHBG concentrations, an effect not observed in alternative therapy for a range of conditions associated with estrogen imbalance including menopausal symptoms, PMS, andendometriosis, as well as prevention of breast and prostate can- Lignans—These compounds are found in fiber-rich foods such
cer and protection against cardiovascular disease and osteoporo- as flaxseed and other oil seeds, whole grains, legumes, and sis.17,42-44 The two main classes of phytoestrogens are the vegetables.53,54 Lignans stimulate the production of SHBG in the liver, and therefore reduce the levels of free estrogen incirculation. They also inhibit aromatase activity, thus decreasing Phytoestrogens beneficially influence estrogen synthesis and the conversion of testosterone and androstenedione into estro- metabolism through a variety of mechanisms: 1.) they have a gens in fat and breast cells.38,46,55 Lignans also have been shown to similar structure to estradiol and can bind to the ER,16,17,43 2.) they inhibit estrogen-sensitive breast cancer cell proliferation.56 increase plasma SHBG levels,45 3.) they decrease aromatase Women consuming 10g of flaxseed per day experienced longer activity,46 and 4.) they shift estrogen metabolism away from the menstrual cycle length, increased progesterone-to-estrogen ratios, and fewer anovulatory cycles, all of which were considered to reflect improved ovarian function.57 Table 2. Mechanisms through which dietary and nutritional factors may influence estrogen metabolism
Mechanism of Action
Promote C-2 hydroxylation over C-4 and/or C-16α hydroxylation Cruciferous vegetables, indole-3-carbinol, rosemary, isoflavones Reduce the oxidation of catechol estrogens (2-OH and 4-OH) Vitamins A, E, & C, N-acetylcysteine, turmeric, green tea,lycopene, α-lipoic acid, flavonoids Promote the methylation of catechol estrogens (2-OH and 4-OH) Folate, vitamins B2, B6, & B12, trimethylglycine, magnesium Increase circulating concentrations of SHBG, thus reducing levels Fiber, lignans (flaxseed), isoflavones (soy, kudzu, clover) Inhibit the activity of aromatase, which converts into estrogens Promote the detoxification of estrogens by upregulating Phase I Turmeric (curcumin), D-limonene, magnesium, vitamins B2, B6, Inhibit the activity of β-glucuronidase, which deconjugates Fiber, probiotics (acidophilus, bifidobacteria), calcium estrogens in the large intestine, allowing them to be reabsorbed Isoflavones (soy, kudzu), lignans (flaxseed), indole-3-carbinol, resveratrol estrogen receptors triggers expression of target genes 2-methoxyestrone and 2-methoxyestradiol - the “good” estrogens: beneficial, balancing fecting growth, health, and function of estrogen responsive Binding to within the cell af tissues (i.e. breast, uterus, ovaries, cervix, prostate, testes, bones, etc.) vitamins E, selenium, curcumin, N-acetylcysteine, green tea catechins (polyphenols), lycopene, S-adenosylhomocysteine, SHBG: sex hormone binding globulin, clover: formononetin, genistein, daidzein -methyltransferase, DHEA: dehydroepiandrosterone, O : N-acetylcysteine, SAM: S-adenosylmethionine, SAH: *Estradiol can be metabolized through the same pathways as estrone.
Nutritional Influences on Estrogen Metabolism Note: type and amounts of macronutrients (protein, carbo- hydrate, and fat support each step in the metabolism Med food for insulin resistance, -lipoic acid,α Resveratrol—This bioflavonoid occurs naturally in grapes and
inhibition, I3C has been shown to prevent the receptor binding of red wine and has been shown to inhibit breast cancer cell growth “stronger,” more stimulating estrogens.70 Other mechanisms in vitro.58 It has been classified as a phytoestrogen based on its relating to I3C’s influence on tissue health involve modulating ability to bind to and activate the ER,59 with recent in vitro stud- ER activity, detoxifying xenoestrogens, modulating cell cycle ies indicating that it exhibits estrogenic and anti-estrogenic activ- regulation, and preventing the adhesion, migration, and invasion ity and binds to ERα and ERβ with comparable affinity.60,61 These estrogen modulatory effects may explain resveratrol’s well-known anticancer and cardioprotective properties.60 B Vitamins
Vitamin E
tant cofactors for enzymes involved in estrogen conjugation and Low serum vitamin E is associated with elevated estrogen levels, methylation. Therefore, decreased levels of B vitamins can dis- and supplementation may reduce symptoms of PMS.62 Vitamin E rupt estrogen detoxification and lead to increased levels of cir- inhibits growth of breast cancer cells, possibly by inhibiting the culating estrogens. For instance, folate (as a precursor to SAM) expression of vascular endothelial growth factor, which encour- is an essential cofactor for the methylation of catechol estrogens, ages angiogenesis.63 Furthermore, vitamin E deficiency may 2-OH and 4-OH, which reduces their conversion to the carcino-negatively affect cytochrome P450 function, thus impacting genic quinones.11 Unfortunately, many individuals have a genetic polymorphism that interferes with their ability to metabolizefolic acid to the active form utilized by the body. Supplementing Magnesium
with a metabolically active form of folate that doesn’t require Magnesium is an essential cofactor for the COMT enzyme, and enzymatic conversion, such as L-5-methyl tetrahydrofolate, will therefore optimizes the methylation and excretion of ensure that these patients maintain adequate folate nutriture.73 catechol estrogens.7 Magnesium also promotes estrogen detoxifi-cation by directly increasing the activity of glucuronyl trans- Another way in which certain B vitamins play a role in estrogen ferase, an enzyme involved in hepatic glucuronidation. Ovarian activity is through a potential to modulate the cell's response to hormones influence magnesium levels, triggering decreases at activation of the ER. It has been demonstrated that elevated intra- certain times during the menstrual cycle as well as altering the cellular concentrations of the active form of vitamin B6 can lead to calcium to magnesium ratio. These cyclical changes can produce significantly decreased gene transcription responses when estrogen many of the well-known symptoms of PMS in women who are binds to the ER.74 By modulating estrogen-induced gene expression in this way, vitamin B6 can attenuate the biological effects ofestrogen. B vitamins also play a role in the prevention of cancer Indole-3-Carbinol (I3C)
because they are crucial for DNA synthesis and repair as well as theprocess of DNA methylation, which is essential for DNA stability I3C is a naturally occurring compound derived from cruciferous and integrity and is an important regulator of gene expression.
vegetables such as broccoli, Brussels sprouts, and cabbage thatactively promotes the breakdown of estrogen to the beneficial Calcium D-Glucarate
metabolite, 2-OH. Therefore, I3C is protective to estrogen-sen-sitive tissues and may be beneficial to those with health issues Calcium D-glucarate is a natural compound that appears to have some influence on breast cancer by aiding in detoxification andthe regulation of estrogen.75 It not only inhibits β-glucuronidase, The mechanism by which I3C promotes 2-OH formation but also increases the activity of the glucuronidation Phase II involves the selective induction of Phase 1 metabolizing pathway, with the net effect of increased estrogen and toxin elim- cytochrome P450 enzymes, which facilitate the 2-hydroxylation ination from the body.76 Calcium D-glucarate has been found in of estrogen.65,66 Through this metabolic role, I3C promotes an animal models to lower estradiol levels and inhibit the initiation, increased ratio of 2-OH to 16α-OH and may improve estrogen metabolism in women with poor diets or impaired detoxifica-tion.3,65,67 I3C may also reduce the activity of the enzyme required Other Beneficial Phytonutrients
for the 4-hydroxylation of estrogen, thereby decreasing carcino- There are many other naturally occurring compounds derived from a variety of plant sources that promote healthy estrogenmetabolism. Curcumin is a polyphenol complex from the curry According to a recent human study in both men and women, spice turmeric, a member of the ginger family. A combination ofsupplementation with 500 mg and 400 mg of I3C, respectively, curcumin and the isoflavone genistein has shown synergy in resulted in significantly increased urinary excretion of 2-OH, reducing xenoestrogen-induced growth of breast cancer cells.77 while that of nearly all other metabolites including estradiol Curcumin also increases hepatic levels of glutathione andand 16α-OH was lower—indicative of their decreased formation.65 induces glutathione-S-transferase (GST) and glucuronyl trans- In another double-blind, placebo-controlled study of 57 women ferase, important in the Phase II detoxification of quinones pro- at increased risk for breast cancer, supplementation with duced from the oxidation of catechol estrogens.78,79 Chrysin is aI3C (300-400 mg/d for 4 weeks) proved to be a promising bioflavonoid that has been shown to inhibit aromatase activity, chemopreventive agent as measured by the increased 2-OH:16α- thus reducing the conversion of androgens into estrogen.80 Aromatase is found in breast tissue, and its inhibition may beuseful in reducing the cell proliferative effects of estrogen.
Not only does I3C promote healthier estrogen metabolism, but it Preliminary research indicates that the herb rosemary promotes may also act as a “weak,” or anti-estrogen. Through competitive the 2-hydroxylation of estrogen in a similar fashion to I3C, and may inhibit 16α hydroxylation. Rosemary may also enhance 34. Basly JP, Marre-Fournier F, Le Bail JC, et al. Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol. Life Sci 2000;66(9):769-77.
35. www.ars-grin/ Dr. Duke’s Phytochemical and Ethnobotanical Databases. November 2000. 36. Shultz TD, Howie BJ. In vitro binding of steroid hormones by natural and purified fibers. Nutr Cancer Furthermore, many antioxidants and phytonutrients can reduce 37. Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and associations.
the oxidation of catechol estrogen metabolites into quinones.
Scand J Clin Lab Invest 1990:50(S201):3-23. 38. Adlercreutz H, Hockerstedt K, Bannwart C, et al. Effect of dietary components, including lignans and phytoestro- Notable players in this group include vitamins E and C, α-lipoic gens, on enterohepatic circulation and liver metabolites of estrogens and in sex hormone binding globulin (SHBG). J acid, N-acetylcysteine, the mineral selenium, curcumin, and Steroid Biochem 1987;27(4-6):1135-44.
39. Musey PI, Collins DC, Bradlow HL, et al. Effect of diet on oxidation of 17 β-estradiol in vivo. J Clin Endocrinol green tea. D-Limonene, a naturally occurring monoterpene 40. Ioannides C. Effect of diet and nutrition on the expression of cytochromes P450. Xenobiotica 1999;29(2):109-54. found in the oils of citrus fruits, promotes the detoxification of 41. Watanabe M. Hypoallergenic rice as a physiologically functional food. Trends Food Sci Tech 1993;4:125-28.
estrogen by inducing Phase I and Phase II enzymes in the liver, 42. Brzezinski A, Debi A. Phytoestrogens: the “natural” selective estrogen receptor modulators? Eur J Obstet Gynecol including GST.82 This compound has also shown great promise in 43. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol 2000;35(6):1403-10.
the prevention and treatment of breast and other cancers.83 44. Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol 1996;87(5):897-904. 45. Pino AM, Valladares LE, Palma MA, et al. Dietary isoflavones affect sex hormone-binding globulin levels in post- menopausal women. J Clin Endocrinol Metab 2000; 85(8): 2797-2800. There are also many hormone-modulating herbs that have a long 46. Wang C, Makela T, Hase T, et al. Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. J Steroid Biochem Molec Biol 1994;50:205-12. history of traditional use in treating women’s health conditions, 47. Xu X, Duncan AM, Merz BE, et al. Effects of soy isoflavones on estrogen and phytoestrogen metabolism in pre- including black cohosh, chasteberry, ginseng, dong quai, and menopausal women. Cancer Epidemiol Biomarkers Prev 1998;7(12):1101-08.
48. Xu X, Duncan AM, Wangen KE, et al. Soy consumption alters endogenous estrogen metabolism in postmenopausal licorice. While the mechanism of action of these herbs varies, women. Cancer Epidemiol Biomarkers Prev 2000; 9(8):781-86.
many have been found to contain phytoestrogens. For a compre- 49. Messina MJ, Persky V, Setchell KD, et al. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr hensive discussion of the use of nutritional supplements and 50. Barnes S, Peterson TG, Coward L. Rationale for the use of genistein-containing soy matrices in chemoprevention herbs in treating PMS, menopause, and other women’s health trials for breast and prostate cancer. J Cell Biochem Suppl 1995;22:181-87.
51. Cassidy A, Bingham S, Setchell KD. Biological effects of a diet of soy protein rich in isoflavones on the menstrual conditions, please refer to the articles titled, Premenstrual cycle of premenopausal women. Am J Clin Nutr 1994; 60(3):333-40. 52. Lu LJ, Anderson KE, Grady JJ, et al. Effects of soya consumption for one month on steroid hormones in pre- Syndrome: A Natural Approach to Management; A Healthy menopausal women: implications for breast cancer risk reduction. Cancer Epidemiol Biomarkers Prev Menstrual Cycle; A Natural Approach to Menopause; and Black 53. Kirkman LM, Lampe JW, Campbell DR, et al. Urinary lignan and isoflavonoid excretion in men and women con- Cohosh and Chasteberry: Herbs Valued by Women for Centuries. suming vegetable and soy diets. Nutr Cancer 1995;24(1):1-12.
54. Thompson LU, Robb P, Serraino M, et al. Mammalian lignan production from various foods. Nutr Cancer 55. Adlercreutz H, Bannwart C, Wahala K, et al. Inhibition of human aromatase by mammalian lignans and isoflavonoid 1. Murray RK, Granner DK, Mayes PA, et al. Harper’s Biochemistry. 24th ed. Stamford (CT): Appleton & Lange; 1996.
phytoestrogens. Steroid Biochem Molec Biol 1993;44(2):147-53. 2. Guyton AC. Textbook of Medical Physiology. 8th ed. Philadelphia: WB Saunders; 1991. 56. Mousavi Y, Adlercreutz H. Enterolactone and estradiol inhibit each other’s proliferative effect on MCF-7 breast can- 3. Bradlow HL, Telang NT, Sepkovic DW, et al. 2-Hydroxyestrone: the ‘good’ estrogen. J Endocrin 1996;150:S259-S65.
cer cells in culture. J Steroid Biochem Mol Biol 1992;41(3-8):615-19.
4. Muti P, Bradlow HL, Micheli A, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 57. Phipps WR, Martini MC, Lampe JW, et al. Effect of flax seed ingestion on the menstrual cycle. J Clin Endocrinol 2:16α-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 2000;11(6):635-40.
5. Yager JD, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 1996;36:203-32. 58. Lu R, Serrero G. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the 6. Westerlind KC, Gibson KJ, Malone P, et al. Differential effects of estrogen metabolites on bone and reproductive tis- growth of human breast cancer cells. J Cell Physiol 1999;179(3):297-304.
sues of ovarectomized rats. J Bone Miner Res 1998;13(6): 1023-31. 59. Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an 7. Bolton JL, Pisha E, Zhang F, et al. Role of quinoids in estrogen carcinogenesis. Chem Res Toxicol agonist for the estrogen receptor. Proc Nat Acad Sci 1997;94:14138-43.
60. Bowers JL, Tyulmenkov V, Jernigan SC, et al. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α 8. Meilahn EN, De Stavola B, Allen DS, et al. Do urinary oestrogen metabolites predict breast cancer? Guernsey III and β. Endocrinology 2000;141(10):3657-67.
cohort follow-up. Br J Cancer 1998;78:1250-55. 61. Bhat KP, Lantvit D, Christov K, et al. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor 9. Fishman J, Osborne MP, Telang NT. The role of estrogen in mammary carcinogenesis. Ann N Y Acad Sci models. Cancer Res 2001;61(20):7456-63.
62. London RS, Murphy L, Kitlowski KE, et al. Efficacy of alpha-tocopherol in the treatment of the premenstrual syn- 10. Zhu BT, Conney AH. Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogene- drome. J Reprod Med 1987;32:400-04.
11. Butterworth M, Lau SS, Monks TJ. 17 β-estradiol metabolism by hamster hepatic microsomes. Implications for the 63. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res 2000;93(1):163-70.
catechol-O-methyl transferase-mediated detoxication of catechol estrogens. Drug Metab Dispos 1996;24(5):588-94. 64. Muneyvirci-Delale O, Nacharaju VL, Altura BM, et al. Sex steroid hormones modulate serum ionized magnesium 12. Yue TL, Wang X, Louden CS, et al. 2-Methoxyestradiol, an endogenous estrogen metabolite, induces apoptosis in and calcium levels throughout the menstrual cycle in women. Fertil Steril 1998;69(5):958-62.
endothelial cells and inhibits angiogenesis: possible role for stress-activated protein kinase signaling pathway and Fas 65. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3- expression. Mol Pharmacol 1997;51(6):951-62. carbinol treatment in humans. J Natl Cancer Inst 1997;89(10):718-23.
13. Fujisawa T, Mori M. Influence of bile salts on β-glucuronidase activity of intestinal bacteria. Lett Appl Microbiol 66. Tiwari RK, Guo L, Bradlow HL, et al. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. J Natl Cancer Inst 1994;86(2):126-31.
14. Severini G, Diana L, Di Giovannandrea R, et al. A study of serum glycosidases in cancer. J Cancer Res Clin Oncol 67. Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer 1991;16(1):59-66. 15. Hambly RJ, Rumney CJ, Fletcher JM, et al. Effects of high- and low-risk diets on gut microflora-associated biomark- 68. Bradlow HL, Sepkovic DW, Telang NT, et al. Multifunctional aspects of the action of indole-3-carbinol as an antitu- ers of colon cancer in human flora-associated rats. Nutr Cancer 1997;27(3):250-53. mor agent. Ann N Y Acad Sci 1999;889:204-13. 16. Cassidy A. Potential tissue selectivity of dietary phytoestrogens and estrogens. Curr Opin Lipidol 1999;10:47-52. 69. Wong GY, Bradlow L, Sepkovic D, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J 17. Kuiper GG, Lemmen JG, Carlsson B, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen Cell Biochem Suppl 1997;28-29:111-16.
receptor β. Endocrinology 1998;139(10):4252-63. 70. Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for pre- 18. Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl vention of cervical cancer. Anticancer Res 1999; 19(3A): 1673-80.
19. Thomas HV, Reeves GK, Key TJ. Endogenous estrogen and postmenopausal breast cancer: a quantitative review.
71. Meng Q, Qi M, Chen DZ, et al. Supression of breast cancer invasion and migration by indole-3-carbinol: associated Cancer Causes Control 1997;8(6):922-28. with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med 2000;78(3):155-65.
20. Rose PG. Endometrial carcinoma. New Eng J Med 1996;335(9):640-49. 72. Riby JE, Chang GH, Firestone GL, et al. Ligand-independent activation of estrogen receptor function by 3,3-diin- 21. Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in post- dolylmethane in human breast cancer cells. Biochem Pharmacol 2000;60(2):167-77. menopausal women. J Natl Cancer Inst 1998;90(17):1292-99. 73. Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Molec Gen Metab 22. Zanetta GM, Webb MJ, Li H, et al. Hyperestrogenism: A relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 2000 Oct;79(1):18-22. 74. Tully DB, Allgood VE, Cidlowski JA. Modulation of steroid receptor-mediated gene expression by vitamin B6.
23. Ursin G, London S, Stanczyk FZ, et al. Urinary 2-hydroxyestrone/16α-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999; 91:1067-72. 75. Minton JP, Walaszek Z, Schooley W, et al. β-Glucuronidase levels in patients with fibrocystic breast disease. Breast 24. Bradlow HL, Davis DL, Lin G, et al. Effects of pesticides on the ratio of 16α/2-hydroxyestrone: a biological marker Cancer Res Treat 1986;8:217-22.
of breast cancer risk. Environ Health Perspect 1995;103 (Suppl 7):147-50.
76. Walaszek Z, Szemraj J, Narog M, et al. Metabolism, uptake, and excretion of a D-glucaric acid salt and its potential 25. Longcope C, Gorbach S, Goldin B, et al. The effect of a low fat diet on estrogen metabolism. J Clin Endocrinol use in cancer prevention. Cancer Detect Prev 1997;21(2):178-90.
77. Verma SP, Goldin BR, Lin PS. The inhibition of the estrogenic effects of pesticides and environmental chemicals by 26. Kerlan V, Dreano Y, Bercovici JP, et al. Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol curcumin and isoflavonoids. Environ Health Perspect 1998;106(12):807-12. in human liver microsomes. Biochem Pharmacol 1992;44(9):1745-56.
78. Goud VK, Polasa K, Krishnaswamy K. Effect of turmeric on xenobiotic metabolising enzymes. Plant Foods Hum 27. Galbraith RA, Michnovicz JJ. The effects of cimetidine on the oxidative metabolism of estradiol. New Engl J Med 79. Susan M, Rao MN. Induction of glutathione S-transferase activity by curcumin in mice. Arzneimittelforschung 28. Kaaks R. Nutrition, hormones, and breast cancer: Is insulin the missing link? Cancer Causes Control 1996;7:605-25. 29. Snedeker SM, Diaugustine RP. Hormonal and environmental factors affecting cell proliferation and neoplasia in the mammary gland. Prog Clin Biol Res 1996;394:211-53. 80. Jeong HJ, Shin YG, Kim IH, et al. Inhibition of aromatase activity by flavonoids. Arch Pharm Res 1999;22(3):309-12.
30. Fan S, Meng Q, Gao B, et al. Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines.
81. Zhu BT, Loder DP, Cai MX, et al. Dietary administration of an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and decreases their uterotropic action in CD-1 mice.
31. Steingraber S. Living Downstream. Reading (MA): Addison-Wesley; 1997.
Carcinogenesis 1998;19(10):1821-27.
32. Zand RS, Jenkins DJ, Diamandis EP. Steroid hormone activity of flavonoids and related compounds. Breast Cancer 82. Maltzman TH, Christou M, Gould MN, et al. Effects of monoterpenoids on in vivo DMBA-DNA adduct formation and on phase I hepatic metabolizing enzymes. Carcinogenesis 1991;12:2081.
33. Scambia G, Ranelletti FO, Benedetti Panici P, et al. Type-II estrogen binding sites in a lymphoblastoid cell line and 83. Vigushin DM, Poon GK, Boddy A, et al. Phase I and pharmacokinetic study of D-limonene in patients with rowth-inhibitory effect of estrogen, anti-estrogen and bioflavonoids. Int J Cancer 1990;46(6):1112-16.
advanced cancer. Cancer Chemother Pharmacol 1998; 42:111-17.
Nutritional Influences on Estrogen Metabolism: A Summary
Estrogen affects the growth, differentiation, and function of tissues much weaker than endogenous estrogens and, through competitive inhi- throughout the body—not just those involved in reproduction. It plays an bition, have been shown to prevent the receptor binding of “stronger,” important role in bone health, protects the cardiovascular system, and more stimulating estrogens.16,17,42 Phytoestrogens are currently under influences behavior and mood. While appropriate levels of estrogens are extensive investigation as a potential alternative therapy for a range of essential for good health, several studies conclude that as exposure to conditions associated with estrogen imbalance, including menopausal estrogen increases, the risk of several cancers, including breast, ovary, symptoms, PMS, endometriosis, prevention of breast and prostate prostate, and thyroid, also increases.7,18-22 Furthermore, excessive estro- cancer, and protection against heart disease and osteoporosis.17,42-44 gen exposure can lead to other health problems such as premenstrual The two main classes of phytoestrogens are isoflavones and lignans. Soy syndrome (PMS), endometriosis, and fibrocystic or painful breasts. is perhaps the most common food source of isoflavones, but other Various lifestyle and environmental factors can influence estrogen pro- excellent sources include legumes, clover, and kudzu root. Higher duction, metabolism, and balance. These include poor diet, obesity, intakes of soy products and isoflavones, such as consumed in traditional excess alcohol consumption, high insulin levels, medications such as Japanese diets, are associated with low rates of hormone-dependent hormone replacement therapy and birth control pills, overexposure to cancers.49 Lignans are compounds found in fiber-rich foods such as chemicals found in pesticides and industrial chemicals, and agricultural flaxseeds, whole grains, legumes, and vegetables.53,54 Lignans stimulate hormones in animal products consumed by humans.17,18,28-31 Genetics can the production of SHBG in the liver, and therefore reduce the levels of also play an important role in determining estrogen levels. free estrogen in circulation. They also inhibit aromatase, an enzyme thatsynthesizes estrogen. THE BASICS OF ESTROGEN METABOLISM
Vitamin E and Magnesium—Low serum vitamin E is associated with
“Estrogen” is a term that is used to collectively describe the female elevated estrogen levels, and may negatively affect estrogen detoxifica- hormones estradiol, estrone, and estriol. The most potent of these is tion. Women with PMS have experienced improvements of their symp- estradiol. Estrogens circulate in the body mainly bound to the sex toms when given supplemental vitamin E.62 Magnesium promotes estro- hormone binding globulin (SHBG) and only unbound estrogens can gen detoxification by promoting methylation and glucuronidation, key enter cells and cause biological effects.1,2 Therefore, any change in the estrogen detoxification pathways. Ovarian hormones influence magne- concentration of SHBG will alter estrogen activity by changing the sium levels, triggering decreases at certain times during the menstrual availability of estrogen to the target cell. cycle as well as altering the calcium to magnesium ratio. These cyclical The ultimate biologic effect of estrogen in the body depends on how it is changes can produce many of the well-known symptoms of PMS in metabolized. The metabolism of estrogen takes place primarily in the women who are deficient in magnesium and/or calcium.64 liver through Phase I (hydroxylation) and Phase II (methylation and Indole-3-Carbinol (I3C)—I3C is a naturally occurring compound
glucuronidation) pathways, which allow the estrogen to be detoxified and derived from cruciferous vegetables that actively promotes the break- excreted from the body. Hydroxylation yields 3 metabolites that vary down of estrogen via the beneficial 2-OH pathway.3,65-67 Therefore, I3C is greatly in biological activity: 2-hydroxyestrone (2-OH), 16α-OH, or protective to estrogen-sensitive tissues and may be beneficial to those 4-OH.3 The 2-OH metabolite is generally termed the “good” estrogen with health issues related to excessive estrogen. Not only does I3C pro- because it generates very weak (and therefore potentially less harmful) mote healthier estrogen metabolism, but it may also act as a “weak” or estrogenic activity in the body. In contrast, the 16α-OH and 4-OH anti-estrogen in a similar fashion to isoflavones.70 metabolites show persistent estrogenic activity and may promote dangerous tissue growth.3-6 In fact, women who metabolize a larger B Vitamins—Folate, B6, and B12 function as important cofactors for
proportion of their estrogen via the 16α-OH metabolite may be at enzymes involved in estrogen detoxification; thus, decreased levels of B significantly higher risk of developing breast cancer.3-5,7-9 Therefore, vitamins can lead to increased levels of circulating estrogens. Certain B shifting estrogen balance toward a less estrogenic state through vitamins also have the potential to modulate the biological effects of promotion of the 2-OH pathway may prove very beneficial in improving estrogen by decreasing the cell’s response when estrogen binds to the a variety of conditions related to elevated or imbalanced estrogen levels. ER.74 B vitamins also play a role in the prevention of cancer because they The 2-OH and 4-OH estrogen metabolites are further detoxified via a are important for DNA synthesis and repair.
process called methylation. This is an important pathway, because it ren- Calcium D-Glucarate—Calcium D-glucarate is a natural compound
ders the harmful 4-OH metabolite significantly less active. Furthermore, found in foods that appears to have some influence on breast cancer by if they are not methylated, the 2-OH and 4-OH estrogens can be con- aiding in detoxification and the regulation of estrogen.75,76 It has been verted to highly reactive molecules that can damage DNA.5,10,11 found in animal models to lower estradiol levels and inhibit the initia- Glucoronidation is one of the key Phase II liver detoxification pathways tion, promotion, and progression of cancer.75 for estrogen, facilitating its elimination from the body.1 OTHER BENEFICIAL PHYTONUTRIENTS AND HERBS
Many other compounds derived from a variety of plant sources are Many elements of good nutrition and diet play an important part in influ- available that promote healthy estrogen metabolism. These include encing estrogen metabolism and detoxification. Incorporating dietary curcumin, a compound found in the herb turmeric (Curcuma longa) that changes with the addition of beneficial nutrients and herbs can increases the phase II detoxification of estrogens;78,79 chrysin, a profoundly affect estrogen balance and potentially reduce the risk of bioflavonoid that inhibits aromatase activity, thus reducing the synthesis estrogen-dependent cancers and other hormone-related conditions. of estrogen;80 the herb, rosemary, which promotes the formation of the Diet—It has been found that dietary interventions such as increasing
2-OH estrogen metabolite;81 and D-limonene from citrus fruits, which consumption of cruciferous vegetables like cabbage and broccoli, and promotes the detoxification of estrogen and shows promise in the foods such as soy can significantly increase the 2-hydroxylation of prevention and treatment of breast and other cancers.82,83 Furthermore, estrogen. Dietary fiber intake can promote the excretion of estrogen by many antioxidant nutrients and phytonutrients can reduce the oxidation binding estrogens in the digestive tract and also increases SHBG, thus of the 2-OH and 4-OH estrogen metabolites. Notable nutrients in this reducing levels of free estradiol.36,38 Complex carbohydrates, such as group include vitamin C, N-acetylcysteine, the mineral selenium, and those found in vegetables and whole grains, are more effective in optimizing estrogen metabolism than simple carbohydrates, which can In addition, traditional societies have long relied on a variety of raise blood glucose and insulin levels, resulting in secondary adverse hormone-modulating herbs in treating women’s health conditions. These include black cohosh, chasteberry, ginseng, dong quai, and licorice. The Phytoestrogens—These plant compounds are similar in shape to the
mechanism of action of these herbs varies; however, many have been estrogen molecule and can bind to estrogen receptors (ERs). They are found to contain beneficial phytoestrogens.


Bisphosphonates in bone disease: from the laboratory to the patient, 2000, 212 pages, herbert fleisch, academic press, 2000, ebook

Bisphosphonates in Bone Disease: From the Laboratory to the Patient, Herbert Fleisch, Academic Press, 2000,0122603702, 9780122603709, 212 pages. This book is an essential handbook on bisphosphonates, the mostwidely used new class of drugs for osteoporosis therapy. It reviews basic physiology in addition to theindications and adverse reactions of these drugs. Bisphosphonates in Bone Disease, 4E,

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