Life Extension Magazine®
There are many misconceptions about what estrogen really is and how it works in the body. This widespread confusion exists in the minds of the lay public as well as the medical community. The result is poor choices being made about what women should be doing to maintain youthful hormone balance while also protecting against cancer. This article uncovers the basic facts about estrogen that are so often overlooked by doctors today. It then reveals dietary modifications that women should consider if they are taking an estrogen drug. The science underlying this article is extremely complex. In order to make this information comprehensible to the lay reader, we have made a special effort to translate these new findings about estrogen metabolism into a version that most people will understand. Nevertheless, some people may have difficulty understanding a few technical areas of this article. This information is so critically important, however, that we urge you to re-read paragraphs you do not understand in order to gain a full grasp of these crucial anticancer concepts. The word estrogen strikes fear into the hearts of many. Women equate it with breast cancer, scientists equate it with “endocrine disruptors,” and doctors equate it with hormone replacement. Are these perceptions accurate? Estrogen is many things. It includes the body’s natural estrogenic hormones and things that look like the body’s natural hormones. As long as something behaves like an estrogen in the body, it is an estrogen, or is, quite simply, “estrogenic.” The strongest natural estrogen in the human body is estradiol. Premarin® is an example of an unnatural estrogen—unnatural, at least, to the human body. It is made from estrogens excreted in the urine of pregnant horses. Chemical estrogens that behave badly once they are inside the body are known as “endocrine disruptors” for their adverse effects on development. All of these estrogens interact with the body’s innate hormonal system. They do not, however, provoke the same responses.
What Makes Estrogen Tick The answer is, partly, estrogen receptors, which are proteins in the body that react to estrogen. Estrogen is like fuel, and estrogen receptors are like machines. When fuel meets machine, things happen. Unfortunately, what happens depends on which area of the body is in question. The receptors of different parts of the body are different. In other words, although all the machinery runs on some type of estrogen, not all the machinery does the same thing. Estrogen does different things in different parts of the body. It does one thing in the brain and another in the breast. It might surprise you to learn, for example, that the pituitary gland is second after the uterus as the most estrogen-responsive area of the body.3 So it is not accurate to think of estrogen as the thing that makes breast cancer cells grow. Just a few years ago, researchers believed that there were two types of estrogen receptors: alpha and beta. That made things fairly simple. Estrogen hits receptor alpha and Y happens. Research focused mostly on the strong estrogen—estradiol—and it seemed that progress could be made in understanding how estrogen affects at least breast tissue, though strange things continued to happen, such as the estrogen “blocker” tamoxifen causing the growth of tamoxifen-dependent cancers. With the discovery of a much larger picture, those days are over and a lot of research is now out the window. As a researcher at Columbia recently lamented, “where will it end?”4 There is more to it than anyone ever imagined. The Plot Thickens Estradiol Stops Cancer Cell Growth In 2001, researchers reported for the first time that tamoxifen breakdown products interact with one of the newly discovered estrogen-receptor-related receptors, and keeps it from activating certain genes normally activated by estrogen.8,15 This opened a whole new vista for understanding how tamoxifen and other synthetic estrogens work. Important clues have already been found. Estrogen Cofactors Discovered In the laboratory, researchers can get estrogen, by itself, to activate estrogen receptors. In other words, in a laboratory setting, any estrogen fuel will activate the estrogen machinery and set things in motion. In real life, this does not happen. In real life, estrogen is only one of many factors that coordinate as a group to activate estrogen receptors. The body makes proteins known as “coactivators” and “corepressors.” These proteins attach themselves to estrogen and other hormones such as thyroid, creating big, complex “globs.” It is these globs—not estrogen alone—that activate or suppress what was previously attributed to estrogen alone. In other words, studies showing what an estrogen does in the laboratory may have little to do with what actually occurs in the human body; in real life, other proteins run the show. This is bold new territory for hormone research. Here is an example of just how important these coactivator and corepressor proteins are in determining how estrogen behaves. Corepressor SSN6 blocks estrogen’s effects in cells. In other words, the SSN6 protein shuts the machinery down. The estrogen fuel can be available (estrogen could be floating all around), but the machinery will not start as long as corepressor SSN6 is working. It neutralizes the effects of estrogen. If something interferes with this protein, however, instead of dampening the effects of estrogen, it enhances them. In addition, estrogen blockers turn into estrogen enhancers.16 Sound familiar? The importance of coactivators and corepressors cannot be overstated. They interact with both estrogen receptors and the newly discovered estrogen-receptor-related receptors. As you will soon read, there may be natural ways for women to regulate these “coactivators” in a manner that reduces breast cancer risk. Estrogen Imposters Premarin® and Prempro™ are drugs made of 17 beta-estradiol and more than a dozen estrogen metabolites from horses.20 These manmade drugs should not be confused with any estrogen manufactured by the human body, with other estrogen drugs, or with estrogen in general. The data from studies of women taking these drugs cannot, and should not, be extrapolated to other hormone replacement drugs or therapy. This is an important point: Premarin® is not estrogen, but instead is an estrogen—one of many estrogens. Different estrogens produce different effects. The manufacturer of Premarin® and Prempro™ has argued that its horse estrogens have unique effects in humans, and undoubtedly they do. Dozens of studies demonstrate important differences between the effects of Premarin® on the human body and the effects of other estrogen products. Transdermal estradiol, for example, may decrease triglycerides and LDL oxidation, whereas Premarin® may do the opposite.21 Premarin® may increase C-reactive protein (a negative for the heart) while transdermal estradiol may not.22 Changing from Premarin® to transdermal estradiol may reduce triglycerides significantly.23 Estrogen patches may reduce blood pressure, whereas oral estrogen may not.24 These and dozens of other studies show different effects depending on which estrogen drug is being evaluated. Not only are there differences between Premarin®/Prempro™ and other drugs, but there are differences between other drugs as well. Neutralizing Estrogen: The Asian Advantage Researchers have extensively investigated three aspects of the Asian advantage: soy, vegetables, and green tea. Each is associated with a dramatically lower risk of breast cancer. Drinking 36 ounces of soy milk a day can reduce levels of estradiol by 20-27% within weeks.32,33 Soy contains isoflavones that neutralize “strong” estrogens, converting them to estrogen metabolites that protect against breast cancer.34 When mice implanted with human breast tumors were given soy concentrate and green tea, tumor size was reduced by 72%.35 Estrogen receptor alpha was also reduced, an indication that the combination of soy and green tea was working at the genetic level, probably with estrogen cofactors. Forty milligrams of isoflavones a day significantly decreased “strong” estrogen levels in women, according to a study from the H. Lee Moffitt Cancer Center in Tampa, FL.36 These are only a few of the many studies demonstrating the beneficial effects of soy. In another experiment that shows the hormonal benefits of soy on the effects of chemical estrogens, when female monkeys were given birth control pills, their cortisol shot up, and their DHEA and testosterone plummeted. When they were given Premarin®, the same thing happened. When the monkeys were given soy protein with isoflavones, however, their hormones normalized.37 Several years ago, there was concern about genistein, an isoflavone in soy, when research showed that it activated estrogen-related genes. Some people took this to mean they should avoid consuming soy, which would be unfortunate given the overwhelmingly positive data about soy’s benefits to humans. Genistein has been called the “good estrogen” for its beneficial effects against estrogen-responsive breast cancer.38 It subsequently emerged that most of the negative research on genistein was generated by one researcher, under conditions that would not exist in real life (such as extremely high levels of genistein put into cancer cells that were deprived of all other estrogen). | |||||
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What You Don't Know About Estrogen | |||||
The human body manufactures estrogen as a necessary component in many processes; estrogen is always in the body, even in postmenopausal women. Copper, too, is always in the body and is another example of something that can distort the way genistein behaves in a test tube.39 Researchers at the University of California, Davis, recently did the same test tube study on genistein and produced the same negative results. They then put genistein in a test tube with the cancer cells and environmental estrogens. The result showed that genistein suppressed cancer cell growth.40 These studies on pure genistein, however, do not accurately reflect what occurs in a complex environment such as the human body. Fortunately, the safety of soy isoflavones (including genistein) for human consumption has been confirmed by experiments with monkeys, the experimental model closest to humans.41 Monkeys treated for three years with soy or soy minus its isoflavones exhibited no abnormal cell growth; in fact, the result was just the opposite. The researchers concluded, “These findings suggest that high dietary levels of soy isoflavones do not stimulate breast or uterine proliferation in postmenopausal monkeys and may contribute to an estrogen profile associated with reduced breast cancer risk.” In addition, a new study clarifying the estrogenic effects of genistein on the uterus found that genistein may enhance cell growth for a few days, but then the effect stops. This is a new finding, and the results are different from those for estrogen drugs that perpetuate growth indefinitely.42 With any luck, issues surrounding how genistein behaves will be soon resolved. It is important to remember that genistein also blocks the growth of estrogen-receptor-negative breast cancer cells. By incorporating soy and isoflavones in her diet, a woman can potentially stop breast cancer before it develops.43 The one caveat is that genistein may interfere with tamoxifen, and thus should not be taken by itself with that drug.44 One of the most exciting new findings is that genistein keeps amyloid from killing brain cells (without any negative effects on uterine cells), and has been suggested as an alternative to synthetic estrogens for the prevention ofAlzheimer’s disease.45 Studies of the popular estrogen drugs Premarin® and Prempro™ show that they may actually increase the risk of dementia.46 Everybody knows that vegetables are good for you, and they are especially good for women who want to avoid breast cancer. Vegetables enable the body to rid itself of excess estrogens. Meat eaters have about 50% more estradiol and estrone in their blood than do vegetarians.47 Women who eat the most vegetables, beans such as lentils, and fiber reduce their risk of breast cancer risk by 50%.48 As you will read next, compounds found in vegetables favorably affect the way estrogen behaves in the body. Other Ways To Tame Estrogen I3C helps convert “strong” estrogens into benign or even helpful estrogens such as 2-hydroxyestrone.50,51 It also acts very much like tamoxifen in blocking undesirable estrogenic effects in breast cancer cells, and its antiestrogen effects are enhanced with genistein.52 When digested, I3C is converted to other substances, including diindolylmethane (DIM). Some earlier research suggested that I3C’s beneficial effects were due to DIM. New research shows this is not the case, and that there are important differences in the effects of I3C and DIM on the metabolism of estrogen. Researchers recently stated, “This finding [of I3C’s effects] is inconsistent with the claim that DIM is the biologically active metabolite of I3C with regard to its antiestrogenicity.” DIM does not increase beneficial 2-hydroxylation of estrogen (at least in rats), but it does lower harmful 4- and 6-hydroxylations.53 By contrast, I3C, which partially converts to DIM during digestion, affects all three in a positive way. Moreover, DIM does not have the anti-estrogen effects of I3C.54 Another potential supplement for breast cancer prevention that has drawn a lot of interest is melatonin. Melatonin is associated with sleep because it builds up during the night, but it may ultimately end up being more associated with estrogen than with sleep. Studies show that melatonin plays a major role in how estrogen behaves. In estrogen-receptor-positive breast cancer cells, melatonin can bring cell growth to a halt.55 Research indicates that melatonin controls estrogen, and vice versa.55-57 In studies of rodents, melatonin shows great promise with regard to its ability to prevent breast cancer when given continuously, before and after exposure to a carcinogen, and when given to mice with the HER2/neu genetic alteration.58,59 Researchers have been unsuccessful in correlating blood levels of melatonin with breast cancer.60 This reflects melatonin’s complexity as a hormone that, like estrogen, comes in various forms and has several receptors. Without a doubt, melatonin plays a major role in breast cancer through its effects on estrogen and other cancer-related phenomena. As an antioxidant, melatonin is not only powerful but also unique. Unlike vitamin E, which essentially has no further effects after it scavenges a radical, when melatonin gets a radical, it creates a new melatonin antioxidant; that is, it self-perpetuates. It also cooperates with other antioxidants like vitamins C and E.61 Antioxidants are very important in preventing cancer, and it has been reported that free radicals can activate or deactivate genes that are involved in breast cancer.62 In addition, melatonin may suppress cortisol, which is a stress-related hormone.63,64 It is interesting to note that the overwhelming majority of breast cancer patients say stress caused their disease.65 In a study of older women, 2 mg of melatonin per day reduced estradiol levels, enhanced sleep, and improved levels of DHEA.66 Melatonin is very potent, and as little as 0.3 mg per day may be enough to produce beneficial effects. Breast cancer is a serious concern for most women. Understanding that there are different types of estrogen, that different estrogens have different effects, and that women can, to a certain degree, control their own estrogen (through dietary modification and supplement use) will help women make informed choices about estrogen exposure and reduce their risk of breast cancer. Recent discoveries about estrogen receptors and how they interact may finally unlock the mysteries of how estrogens work, and provide the basis for nontoxic treatment and effective prevention.
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What You Don't Know About Estrogen | ||
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References | ||
1. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol. 1991 Feb;9(2):286-94. 2. Love RR, Barden HS, Mazess RB, Epstein S, Chappell RJ. Effect of tamoxifen on lumbar spine bone mineral density in post- menopausal women after 5 years. Arch Intern Med. 1994 Nov 28;154(22):2585-8. 3. Jelinsky SA, Harris HA, Brown EL, et al. Global transcription profiling of estrogen activity: estrogen receptor alpha regulates gene expression in the kidney. Endocrinology. 2003 Feb;144(2):701-10. 4. Toran-Allerand CD. Minireview: a plethora of estrogen receptors in the brain: where will it end? Endocrinology. 2004 Mar;145(3):1069-74. 5. Wilkinson HA, Dahlund J, Liu H, et al. Identification and characterization of a functionally distinct form of human estrogen receptor beta. Endocrinology. 2002 Apr;143(4):1558-61. 6. Horard B, Vanacker JM. Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. J Mol Endocrinol. 2003 Dec;31(3):349-57. 7. Greschik H, Wurtz JM, Sanglier S, et al. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell. 2002 Feb;9(2):303-13. 8. Tremblay GB, Bergeron D, Giguere V. 4- hydroxytamoxifen is an isoform-specific inhibitor of orphan estrogen-receptor-related (ERR) nuclear receptors beta and gamma. Endocrinology. 2001 Oct;142(10):4572-5. 9. Yang C, Chen S. Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. Cancer Res. 1999 Sep 15;59(18):4519-24. 10. Osipo C, Gajdos C, Liu H, Chen B, Jordan VC. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer. J Natl Cancer Inst. 2003 Nov 5;95(21):1597-08. 11. Stoll BA. Palliation by castration or by hormone administration. In: Stoll BA, ed. Breast Cancer Management. London: William Heineman; 1977:133-46. 12. Stoll BA. Overprolonged adjuvant tamoxifen therapy in breast cancer. Ann Oncol. 1991 Jun;2(6):401-3. 13. Howell A, Dodwell DJ, Anderson H, Redford J. Response after withdrawal of tamoxifen and preogestogens in advanced breast cancer. Ann Oncol. 1992 Sep;3(8):611-7. 14. Schafer JM, Lee ES, O’Regan RM, Yao K, Jordan VC. Rapid development of tamoxifen-stimulated mutant p53 breast tumors (T47D) in athymic mice. Clin Cancer Res. 2000 Nov;6(11):4373-80. 15. Coward P, Lee D, Hull MV, Lehman JM. 4- Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc Natl Acad Sci. 2001Jul 17;98(15):8880-4. 16. McDonnell DP, Vegeto E, O’Malley BW. Identification of a negative regulatory func- tion for steroid receptors. Proc Natl Acad Sci. 1992 Nov 15;89(22):10563-67. 17. Takahashi K, Okada M, Ozaki T, et al. Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod. 2000 May;15(5):1028-36. 18. Iosif CS. Effects of protracted administration of estriol on the lower genito urinary tract in postmenopausal women. Arch Gynecol Obstet. 1992;251(3):115-20. 19. Head KA. Estriol: safety and efficacy. Altern Med Rev. 1998 Apr;3(2):101-13. 20. Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estro- gens and their potntial role in the prevention of neurodegenerative diseases such as Alzheimer’s. J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):473-82. 21. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative suscepti- bility of low-density lipoprotein particles in postmenopausal women. Circulation. 2002 Oct 1;106(14):1771-6. 22. Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol. 2003 Apr 16;41(8):1358-63. 23. Sanada M, Tsuda M, Kodama I, Sakashita T, Nakagawa H, Ohama K. Substitution of transdermal estradiol during oral estrogen- progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause. 2004 May;11(3):331-6. 24. Akkad AA, Halligan AW, Abrams K, al Azzawi F. Differing responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapy. Obstet Gynecol. 1997 Jan;89(1):97-03. 25. Shimizu H, Ross RK, Bernstein L, et al. Serum oestrogen levels in postmenopausal women: comparison of American whites and Japanese in Japan. Br J Cancer. 1990;62(3):451-3. 26. Hill P, Chan P, Cohen L, Wynder E, Kuno K. Diet and endocrine-related cancer. Cancer. 1977 Apr; 39(4 Suppl):1820-6. 27. Dickinson LE, Macmahon B, Cole P, Brown JB. Estrogen profiles of Oriental and Caucasian women in Hawaii. N Engl J Med. 1974 Dec 5;291(23):1211-3. 28. Lawson JS, Field AS, Tran DD, et al. Breast cancer incidence and estrogen receptor alpha in normal mammary tissue–an epi- demiologic study among Japanese women in Japan and Hawaii. Int J Cancer. 2002 Feb 10;97(5):685-7. 29. de Visser SJ, Uchida N, Vliet- Daskalopoulou E, et al. Pharmacokinetic differences between Caucasian and Japanese subjects after single and multiple doses of a potential combined oral contraceptive (Org 30659 and EE). Contraception. 2003 Sep;68(3):195-02. 30. Punnonen R, Lukola A, Kudo R. Cytoplasmic estrogen receptor concentrations in the endometrium of Finnish and Japanese women. Eur J Obstet Gynecol Reprod Biol.1984 Jul;17(5):321-5. 31. Moore JW, Clark GM, Takatani O, Wakabayashi Y, Hayward JL, Bulbrook RD. Distribution of 17 beta-estradiol in the sera of normal British and Japanese women. J Natl Cancer Inst. 1983 Oct;71(4):749-54. 32. Nagata C, Takatsuka N, Inaba S, Kawakami N, Shimizu H. Effect of soymilk consumption on serum estrogen concentrations in premenopausal Japanese women. J Natl Cancer Inst. 1998 Dec 2;90(23):1830-5. 33. Lu LJ, Anderson KE, Grady JJ, Nagamani M. Effects of an isoflavone-free soy diet on ovarian hormones in premenopausal women. J Clin Encodrinol Metab. 2001 Jul;86(7):3045-52. 34. Lu LJ, Cree M, Josyula S, Nagamani M, Grady JJ, Anderson KE. Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones. Cancer Res. 2000 Mar 1;60(5):1299-05. 35. Zhou JR, Yu L, Mai Z, Blackburn GL. Combined inhibition of estrogen dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer. 2004 Jan 1;108(1):8-14. 36. Kumar NB, Cantor A, Allen K, Riccardi D, Cox CE. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer. 2002 Feb 15;94(4):1166-74. 37. Wood CE, Cline JM, Anthony MS, Register TC, Kaplan JR. Adrenocortical effects of oral estrogens and soy isoflavones in female monkeys. J Clin Endocrinol Metab. 2004 May;89(5):2319-25. 38. Shao ZM, Shen ZZ, Fontana JA, Barsky SH. Genistein’s “ER-dependent and independent” actions are mediated through ER pathways in ER-positive breast carcinoma cell lines. Anticancer Res. 2000 Jul;20(4):2409-16. 39. Verma SP, Goldin BR. Copper modulates activities of genistein, nitric oxide, and cur- cumin in breast tumor cells. Biochem Ciophys Res Commun. 2003 Oct 10;310(1):104-8. 40. Han DH, Denision MS, Yamada K. Relationship between estrogen receptor- binding and estrogenic activities of environmental estrogens and suppression by flavi- noids. Biosci Biotechnol Biochem. 2002 Jul;66(7):1479-87. 41. Wood CE, Register TC, Anthony MS, Kock ND, Cline JM. Breast and uterine effects of soy isoflavones and conjugated equine estro- gens in postmenopausal female monkeys. J Clin Endocrinol Metab. 2004 Jul;89(7):3462- 8. 42. Diel P, Geis R-B, Caldarelli A, et al. The differential ability of the phytoestrogen genis- tein and of estradiol to induce uterine weight and proliferatin in the rat is associated with a substance specific modulation of uterine gene expression. Mol Cell Endocrin. 2004 Jun 30;221(1-2):21-32. 43. Peterson G, Barnes S. Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. Cell Growth Differ. 1996 Oct;7(10):1345-51. 44. Ju YH, Doerge DR, Allred KF, Alfred CD, Helferich WG. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. 2002 May 1;62(9):2474-7. 45. Bang OY, Hong HS, Kim DH, et al. Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiol Dis. 2004 Jun;16(1):21-8. 46. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. 47. Djuric Z, Depper JB, Uhley V, Smith D, Lababidi S, Martino S, Heilbrun LK. Oxidative DNA damage levels in blood from women at high risk for breast cancer are associated with dietary intakes of meats, veetables, and fruits. J Am Diet Assoc. 1998 May;98(5):524-8. 48. Dos Santos SI, Mangtani P, McCormack V, et al. Lifelong vegetarianism and risk of breast cancer: a population-based case-control study among South Asian migrant women living in England. Int J Cancer 2002; 99:238-44. 49. Hecht SS, Carmella SG, Kenney PM, Low SH, Arakawa K, Yu MC. Effects of cruciferous vegetable consumption on urinary metabolites of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone in Singapore Chinese. Cancer Epidemiol Bio Prev. 2004 JuN;13(6):997-04. 50. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21;89(10):718-23. 51. Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol. 1996 Sep;150 Suppl:S259-65. 52. Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003 Jul;133(7 Suppl):2407S-75. 53. Parkin DR, Malejka-Giganti D. Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3’diindolylmethane and its parent compound indole-3-carbinol. Cancer Detect Prev.2004 ;28(1):72-9. 54. Gao X, Petroff BK, Oluola O, Georg G, Terranova PF, Rozman KK. Endocrine disruption by indole-3-carbinol and Tamoxifen: blockage of ovulation. Toxic App Pharmacol. 2002 Sep 15;183(3):179-88. 55. Girgert R, Bartsch C, Hill SM, Kreienberg R, Hanf V. Tracking the elusive antiestrogenic effect of melatonin: a new methodological approach. Neuro Endocrinol Lett. 2003 Dec;24(6):440-4. 56. Rato AG, Pedrero AG, Martinez MA, del Rio B, Lazo PS, Ramos S. Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J. 1999 May;13(8):857-68. 57. Luboshitzky R, Here P, Shen-Orr Z. Urinary 6-sulfaoxymelatonin excretion in hyperan drogenic women: the effect of cyproterone acetate-ethinyl estradiol treatment. Exp Clin Endocrinol Diabetes. 2004 Feb;112(2):102-7. 58. Anisimov VN, Alimova IN, Baturin DA, et al. The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice. Int J Cancer. 2003 Jan 20;103(3):300-5. 59. De Jonage-Canonico MB, Lenoir V, Martin A, Scholler R, Kerdelhue B. Long term inhibition by estradiol or progesterone of mela- tonin secretion after administration of a mammary carcinogen, the dimethyl benz(a)anthracene, in Sprague-Dawley female rat; inhibitory effect of melatonin on mammary carcinogenesis. Breast Cancer Res Treat. 2003 Jun;79(3):365-77. 60. Travis RC, Allen DS, Fentiman IS, Key TJ. Melatonin and breast cancer: a prospective study. J Natl Cancer Inst. 2004 Mar 17;96(6):475-82. 61. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Significance of melatonin in antioxidative defense system: reactions and products. Biol Signals Recept. 2000 May;9(3-4):137-59. 62. Chuang YY, Chen Y, Gadisetti, et al. Gene expression after treatment with hydrogen-peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54. 63. Torres-Farfan C, Richter HG, Rojas-Garcia P, et al. Mt1 melatonin receptor in the primate adrenal gland: inhibition of adrenocorti-cotropin-stimulated cortisol production by melatonin. J Clin Endocrinol Metab. 2003 Jan;88(1):450-8. 64. Cagnacci A, Soldani R, Yen SS. Melatonin enhances cortisol levels in aged but not young women. Eur J Endocrinol. 1995 Dec;133(6):691-5. 65. Stewart DE, Cheung AM, Duff S, et al. Attributions of cause and recurrence in long-term breast cancer survivors. Psychooncology. 2001 Mar;10(2):179-83. 66. Pawlikowski M, Kolomecka M, Wojtczak A, Karasek M. Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women. Neuro Endocrinol Lett. 2002 Apr;23 Suppl 1:17-19. 67. Available at: http://www.OurStolenFuture.org. Accessed August 9, 2004. 68. No authors. Oral-contraceptive use and the risk of breast cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med. 1986 Aug 14;315(7):405-11. 69. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999 Jan 14;340(2):77-84. 70. Chang-Claude U. Inherited genetic suscep tibility to breast cancer. IARC Sci Publ. 2001;154:177-90. 71. Houlston RS, Tomlinson IP. Modifier genes in humans: strategies for identification. Eur J Hum Genet. 1998 Jan;6(1):80-8. 72. Houlston RS, Tomlinson IP. Detecting low penetrance genes in cancer: the way ahead. J Med Genet. 2000 Mar;37(3):161-7. 73. Brandt B, Hermann S, Straif K, Tidow N, Buerger H, Chang-Claude J. Modification of breast cancer risk in young women by a polymorphic sequence in the egfr gene. Cancer Res. 2004 Jan 1;64(1):7-12. 74. Shannon J, Cook LS, Stanford JL. Dietary intake and risk of postmenopausal breast cancer (United States). Cancer Causes Control. 2003 Feb;14(1):19-27. 75. Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Dietary effects on breast cancer risk in Singapore. Lancet. 1991 May 18;337(8751):1197-1200. 76. Dos Santos SI, Mangtani P, McCormack V, et al. Lifelong vegetarianism and risk of breast cancer: a population-based case-control study among South Asian migrant women living in England. Int J Cancer. 2002; 99:238-44. 77. Toniolo P, Riboli E, Shore RE, Pasternack BS. Consumption of meat, animal products, protein, and fat and risk of breast cancer: a prospective cohort study in New York. Epidemiology. 1994 Jul;5(4):391-7. 78. Cho E, Spiegelman D, Hunter DJ, et al. Premenopausal fat intake and risk of breast cancer. J Natl Cancer Inst. 2003 Jul 16;95(14):1079-85. 79. Le MG, Moulton LH, Hill C, Kramar A. Consumption of dairy produce and alcohol in a case-control study of breast cancer. J Natl Cancer Inst. 1986 Sep;77(3):633-6. 80. Djuric Z, Depper JB, Uhley V, Smith D, Lababidi S, Martino S, Heilbrun LK. Oxidative DNA damage levels in blood from women at high risk for breast cancer are associated with dietary intakes of meats, veg- etables, and fruits. J Am Diet Assoc. 1998 May;98(5):524-8. 81. Available at: http://www.thebreastcancer fund.org. Accessed August 9, 2004. 82. Available at: http://www-dep.iarc.fr/globo can/globocan.html. Accessed August 9, 2004. 83. Available at: http://www.ianr.unl.edu/pubs/ Feef/g1324.htm. Accessed August 9, 2004. 84. Maume D, Deceuninck Y, Pouponneau K, Paris A, LeBizec B, Andre F. Assessment of estradiol and its metabolites in meat. APMIS. 2001 Jan;109(1):32-8. 85. Reyes N, Iatropoulos M, Mittelman A, Geliebter J. Microarray analysis of diet-induced alterations in gene expression in the ACI rat prostate. Eur J Cancer Prev. 2002 Aug;11 Suppl 2:S37-42. 86. Lu LJ, Cree M, Josyula S, Nagamani M, Grady JJ, Anderson KE. Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones. Cancer Res. 2000 Mar 1;60(5):1299-05. 87. Liu S, Kulp SK, Sugimoto Y, Jiang J, Chang HL, Lin YC. Involvement of breast epithe- lial-stromal interactions in the regulation of protein tyrosine phosphatase-gamma (PTPgamma) mRNA expression by estrogenically active agents. Breast Can Res Treat. 2002 Jan;71(1):21-35. 88. Chen CL, Weiss NS, Newcomb P, Barlow W, White E. Hormone replacement therapy in relation to breast cancer. JAMA. 2002 Feb 13;287(6):734-41. 89. O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst. 2001 May 16;93(10):754-62. 90. Cobleigh MA, Berris RF, Bush T, et al. Estrogen replacement therapy in breast can- cer survivors. A time for change. Breast Cancer Committees of the Eastern Cooperative Oncology Group. JAMA. 1994 Aug 17;272(7):540-5. 91. Vassilopoulou-Sellin R, Cohen DS, Hortobagyi GN, et al. Estrogen replacement therapy for menopausal women with a history of breast carcinoma. Results of a 5-year, prospective study. Cancer. 2002 Nov 1;95(9):1817-26. 92. Peters GN, Fodera T, Sabol J, et al. Estrogen replacement therapy after breast cancer: a 12-year follow-up. Ann Surg Oncol. 2001 Dec;8(10):828-32. 93. Col NF, Hirota Lk, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol. 2001 Apr 15;19(8):2357-63. 94. Meurer LN, Lena S. Cancer recurrence and mortality in women using hormone replacement therapy: meta-analysis. J Fam Pract. 2002 Dec;51(12):1056-62. 95. Brewster WR, SiSaia PJ, Grosen EA, Mc Gonigle KF, Kuykendall JL, Creasman WT. An experience with estrogen replacement therapy in breast cancer survivors. Int J Fertil Womens Med. 1999 Jun;44(4):186-92. 96. Guidozzi F. Estrogen replacement therapy in breast cancer survivors. Int J Gynaecol Obstet. 1999 Jan;64(1):59-63. 97. Stahlberg C, Pedersen AT, Lynge E, et al. Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe. Int J Cancer. 2004 May 1;109(5):721-7. 98. Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von Schoultz B. Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transder-mal and low-potency estrogen regimens. Climacteric. 2001 Mar;4(1):42-8. 99. Maunsell E, Drolet M, Brisson J, Robert J, Deschenes L. Dietary change after breast cancer: extent, predictors, and relation with psychological distress. J Clin Oncol. 2002 Feb 15;20(4):1017-25. 100. Patterson RE, Neuhouser ML, Hedderson MM, et al. Types of alternative medicine used by patients with breast, colon, or prostate cancer: predictors, motives, and costs. J Altern Complement Med. 2002 Aug;8(4):477-85. 101. Harris PF, Remington PL, Trentham-Dietz A, Allen CI, Newcomb PA. Prevalence and treatment of menopausal symptoms among breast cancer survivors. J Pain Symptom Manage. 2002 Jun;23(6):501-9. |