Life Extension Magazine®

The Estrogen Dilemma

Numerous studies link estrogen drugs to increased risk of heart attack, stroke, and cancer. Plant-based phytoestrogens and lignans may provide menopausal relief while protecting against osteoporosis, cardiovascular diseases, and certain cancers.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written by: William Faloon.

by William Faloon

Over the past five years, it has been hard to find anything positive about estrogen drugs. In one scientific study after another, estrogen drugs have been shown to increase the risks of heart attack,1-6 stroke,2-7 dementia,8-11 and several prevalent forms of cancer.11-28

The media has turned these horrific estrogen studies into headline news stories. Understandably, most women now refuse to take estrogen drugs. To add fuel to the fire, the maker of Premarin® ran television commercials promoting the benefit of its estrogen drug in alleviating menopausal symptoms. These Premarin® commercials, however, itemized all of the lethal diseases caused by estrogen drugs, leaving one to wonder what purpose the manufacturer had in running such ads.

While estrogen drugs have been justifiably vilified, the media has ignored a plethora of new studies showing that phytoestrogens (estrogen-like plant compounds) may protect against the most common disorders faced by aging women, including breast cancer,29-35 osteoporosis,36-41 and cardiovascular disease.42-45

Phytoestrogens Reduce Lung Cancer Risk

When the Journal of the American Medical Association publishes a study about a nutrient, be it positive or negative, the media usually reports on it. Not so with a study published in September 2005 that showed that those who consumed the most phytoestrogens reduced their lung cancer risk by an astounding 46%.46

Non-smokers mistakenly think they are not at risk for contracting lung cancer. Yet there are more than 30,000 lung cancer deaths each year in non-smoking Americans.47 The fact that so many smokers contract lung cancer deceives the public into ignoring the high prevalence of lung cancer that exists throughout the population.

The conclusion from this latest study published by the American Medical Association was that these data “provide further support for the limited but growing epidemiologic evidence that phytoestrogens are associated with a decrease in risk of lung cancer.”46

Interestingly, while doctors debate whether phyto-estrogens can prevent breast cancer, few experts connect phytoestrogens with lung cancer. Yet several published studies now show that consumption of phytoestrogens is associated with reductions in lung cancer incidence.46,48-50

Why Phytoestrogens Are Popular Today

Studies on the dietary habits of large population groups (epidemiological data) suggest that consumption of phytoestrogens can be protective against the development of breast,51-54 prostate,55-57 and other cancers.58,59 Other studies show that phytoestrogens reduce vascular disease risk60-64 and help maintain bone density.35-41

Newly published studies reveal the specific mechanisms by which phytoestrogens protect against the most feared diseases of aging.30,65-68 This explanatory laboratory data, which support the favorable epidemiological studies, are leading a growing number of re-searchers to publish favorable review articles about the health benefits of phytoestrogens.69-79

Women consume various phytoestrogen preparations seeking symptomatic menopausal relief. Some studies show positive effects in relieving menopausal miseries, while other studies show no benefit.80-82 This conflicting efficacy data relating to menopause can be explained by the individual needs menopausal women have for estrogen, progesterone, DHEA, pregnenolone, and other hormones.

Testing a single phytoestrogen compound is unlikely to benefit enough menopausal women to yield statistically significant results in a controlled study. An ideal investigation would test each study participant’s blood, and then restore levels of all the hormones lost to aging to more youthful ranges. Conventional medicine remains caught up in testing one hormone compound on a group of women, even though it is an established fact that each individual’s hormone replacement needs differ markedly.

A Complex Predicament

As women enter the menopausal years, they face a difficult decision. The body’s natural production of estrogen, progesterone, DHEA, and other critical hormones needed to maintain health and vigor rapidly declines. While individual effects of menopause vary, most women suffer because their glands no longer produce the hormones needed to regulate critical physiological processes. Depression, irritability, and short-term memory lapses are common menopausal complaints, along with hot flashes, night sweats, and insomnia.

An overwhelming body of scientific evidence shows that commonly prescribed estrogen drugs (such as Premarin® and Prempro®) increase the incidence of heart attack, stroke, breast and ovarian cancers, and other diseases.1-28 More and more women are switching to “natural” estrogen drugs in the hope of deriving estrogen’s anti-aging benefits without the lethal side effects of commonly prescribed hormone drugs.

Recognizing that even natural estrogen drugs stimulate breast cell proliferation, proponents of natural estrogen replacement advocate consumption of cancer-preventing fruits and vegetables, along with supplements such as indole-3-carbinol,83-97 resveratrol,98-108 gamma tocopherol,109-113 melatonin,114-120 genistein,121-144 and others. The potential cancer-preventive effects of these supplements are substantiated in the scientific literature, but it is not known for sure if these nutrients confer absolute protection against estrogen drug-induced cancers.

Those who advocate the use of natural estrogen drugs argue that young women who secrete higher levels of estrogen do not have high incidences of breast or ovarian cancers. The overlooked factor is that younger women have fewer DNA gene mutations than older women, making younger women less vulnerable to the carcinogenic effects of estrogen than older women. As women’s breast and other cells age, they acquire more mutations in genes that regulate cellular proliferation.145,146 This makes aging women’s cells more vulnerable to the stimulatory (carcinogenic) effects of estrogen, be it bioidentical estrogen drugs like Biest and Estrace® or horse urine-derived estrogens such as Premarin®.

New Hope for Aging Women

The debate about the safety of bioidentical estrogen replacement therapy continues unabated. Yet a remarkable number of new studies indicates that proper consumption of plant-based phyto-estrogens and lignans may provide menopausal relief while also protecting against osteoporosis, cardiovascular diseases, and certain cancers.36,38,40,80-82,131,147-154

In this month’s issue, we summarize new findings about phyto-estrogens in order to provide a scientific rationale for women of all ages to enjoy the youth-restoring benefits attainable with proper female hormone balancing.

As a member of the Life Extension Foundation, you gain access to in-depth analyses of complex medical issues that are understandable to the lay reader. If you had to rely on the media or hurried doctors for this type of information, you would get only a small part of the story. Life Extension members have the benefit of discovering the collective experiences of physicians and scientists who have utilized safe, natural hormone replacement approaches for many decades.

For longer life,

William Faloon

Despite more than a decade’s worth of research showing that taking too much of a popular pain reliever can ruin the liver, the number of severe, unintentional poisonings from the drug is on the rise, a new study reports. The drug, acetaminophen, is best known under the brand name Tylenol.® But many consumers don’t realize that it is also found in widely varying doses in several hundred common cold remedies and combination pain relievers.

These compounds include Excedrin®, Midol® Teen Formula, Theraflu®, Alka-Seltzer Plus® Cold Medicine, and NyQuil® Cold and Flu, as well as other over-the-counter drugs and many prescription narcotics, like Vicodin® and Percocet®.

The authors of the study, which is appearing in the December issue of Hepatology, say the combination of acetaminophen’s quiet ubiquity in over-the-counter remedies and its pairing with narcotics in potentially addictive drugs like Vicodin® and Percocet® can make it too easy for some patients to swallow much more than the maximum recommended dose inadvertently.

“It’s extremely frustrating to see people come into the hospital who felt fine several days ago, but now need a new liver,” said Dr. Tim Davern, one of the authors and a gastroenterologist with the liver transplant program of the University of California at San Francisco. “Most had no idea that what they were taking could have that sort of effect.” The numbers of poisonings, however, are still tiny in comparison with the millions of people who use over-the-counter and prescription drugs with acetaminophen.

Dr. Davern and a team of colleagues from other centers led by Dr. Anne Larson at the University of Washington Medical Center in Seattle, tracked the 662 consecutive patients who showed up with acute liver failure at 23 transplant centers across the United States from 1998 to 2003.

Acetaminophen poisoning was to blame in nearly half the patients, the scientists found. The proportion of cases linked to the drug rose to 51% in 2003 from 28% in 1998. Not all the poisonings were accidental. An estimated 44% were suicide attempts by people who swallowed fistfuls of pills. “It’s a grisly way to die,” Dr. Davern said, adding that patients who survive sometimes suffer profound brain damage.

But in at least another 48% of the cases studied, the liver failed after a smaller, unintentional assault by the drug over several days. “I see some young women who have been suffering flulike symptoms for the better part of a week, and not eating much,” Dr. Davern said. “They start with Tylenol®, and maybe add an over-the-counter flu medicine on top of that, and pretty soon they’ve been taking maybe six grams of acetaminophen a day for a number of days. In rare cases that can be enough to throw them into liver failure.”

Each Extra Strength Tylenol® tablet contains half a gram, or 500 milligrams, of acetaminophen, and arthritis-strength versions of the pain reliever contain 650 milligrams. One tablet of Midol® Teen Formula contains 500 milligrams of acetaminophen, as does one adult dose of NyQuil® Cold and Flu. One dose of Tylenol® Cold and Flu Severe contains 1,000 milligrams. The recommended maximum daily dose for adults is 4 grams, or 4,000 milligrams.

“Part of the problem is that the labeling on many of these drugs is still crummy,” said Dr. William Lee, a liver specialist at the University of Texas Southwestern Medical Center in Dallas, who for years has been lobbying the Food and Drug Administration to make manufacturers put “acetaminophen” in large letters on the front of any package that contains it, so that as they reach for the bottle, patients will be more likely to pause and keep track of exactly how much they are swallowing.

Some companies have voluntarily added new warnings about acetaminophen’s risk to the liver, and they should be given credit for that, said Dr. Charles Ganley, director of the FDA’s Office of Nonprescription Products. “But labeling isn’t where I would like it to be,” Dr. Ganley added.

McNeil Consumer & Specialty Pharmaceuticals, a division of Johnson & Johnson, updated the labeling on all its Tylenol® products in 2002 to list all the active ingredients on the front of the bottle, increase the type size of acetaminophen, and add a label on the front warning consumers not to use the product with others that contain acetaminophen, said Kathy Fallon, a spokeswoman.

“I urge consumers to read the label,” she said. “Anything more than the recommended dose is an overdose.”

Dr. Lee said he was disturbed by a pattern: “that acetaminophen is always billed as the one to reach to for safety, probably even more so now, with other pain relievers pulled from the market.”

In fact, the drug, when given in precise, appropriate doses, is safer for children and teenagers than aspirin, which can interact with a viral infection to bring on rare but serious damage to the brain, liver, and other organs in a constellation of symptoms known as Reye’s syndrome. And among adults, low doses of acetaminophen are less likely than aspirin, ibuprofen, or naproxen to eat away at the stomach, aggravate bleeding, or harm the kidneys.

Even patients with chronic liver disease are justly advised to take acetaminophen for the occasional fever, or for the pain of osteoarthritis, a back injury, or other malady, if they keep the total daily dose under about two grams, Dr. Lee said.

Experts agree that a vast majority of people can safely take the four-gram daily maximum that labels recommend for adults—the equivalent of eight Extra Strength Tylenol® spread across 24 hours—and some people swallow much more without harm.

But by eight grams in a single day, a significant number of people whose livers have been stressed by a virus, medication, alcohol, or other factors would run into serious trouble, Dr. Lee said. Without intervention, about half the people who swallowed a single dose of 12 to 15 grams could die.

How much alcohol over what time period is problematic? Recent research suggests the answer isn’t simple. The package labels now warn anyone who drinks three or more drinks every day to consult a doctor before taking acetaminophen, but Dr. Lee thinks that people who are sober during the week but binge on weekends may be vulnerable, too.

The few days of fasting that can accompany a bad stomach bug also seem to increase the liver’s vulnerability to acetaminophen. And though safe levels of the drug for large men may, in general, be higher than those for small women, obese people aren’t protected; extra fat in the liver seems to prime the organ for further damage.

Nearly two thirds of the people in the transplant center study who unintentionally poisoned themselves were taking one or another of the roughly 200 prescription drugs that contain acetaminophen plus an opiate. Among the most popularly prescribed drugs in this group include hydrocodone bitartrate plus acetaminophen, which is commonly sold as Vicodin®, and oxycodone hydrochloride plus acetaminophen, better known as Percocet®.

While these acetaminophen/ opiate combination drugs can be very effective in curbing pain after surgery or injury, some patients who take the drugs chronically soon find they need increasing amounts to achieve the same level of pain relief.

Because the narcotic part of the compound can be addictive, its accompanying doses of acetaminophen climb sky high in lock step. The liver may keep pace with gradual increases of the drug initially, only to suddenly crash months later. It is the acetaminophen that kills the liver.

Lynne Gong of San Jose, Calif., watched her 28-year-old daughter, Leah, nearly die last summer after that sort of crash. What had started out as a treatment for the pain of a dislocated shoulder and subsequent surgery had escalated over two years to a full-blown addiction.

After her daughter was hospitalized, Ms. Gong said she found herself warning friends, neighbors “and anyone else who would listen” that they needed to closely monitor their own intake of acetaminophen and that of their children.

Some dangers lurk in surprising corners. One day, after Lynne Gong told the women in her prayer group about Leah’s experience, a member went home and, after a little investigating of her own, discovered that her 12-year-old son and his friends had started nipping NyQuil® on Friday nights for the alcohol content, in hopes of getting drunk.

There are 9.8 grams of acetaminophen in a 10-ounce bottle of NyQuil®, Ms. Gong said. “Everyone really needs to be more aware.”

Copyright (2005) By the New York Times Co. Reprinted with permission.

Acetaminophen Even More Dangerous Than Previously Reported

The New York Times has reported on a new study that shows that acetaminophen is even more toxic than previously thought. According to a new study published in the journal Hepatology, acetaminophen is the number-one cause of acute liver failure.155 In classic acute liver failure, the patient either obtains an emergency liver transplant or dies.

On January 22, 2004, the FDA confirmed what Life Extension members have long known—that acetaminophen is extremely dangerous.156 Acetaminophen is sold under the brand name Tylenol® and is contained in more than 600 other drug products. Life Extension revealed the toxicity of acetaminophen more than 14 years ago. We harshly criticized the FDA for not mandating that the labels of acetaminophen products warn those with liver or kidney problems to avoid the drug.

Four years ago, an FDA scientific advisory committee urged that warnings be put on the labels of acetaminophen drugs.157,158 Despite overwhelming documentation confirming acetaminophen’s toxicity,159-182 the FDA said no to its own scientific advisors. Instead, the agency budgeted a mere $20,000183,184 to develop material that it hoped would be run in major magazines and distributed by pharmacy chains for free!

Back in 1992, we warned that more people were dying from acetaminophen poisoning than the numbers indicated by the official statistics. While the FDA was preoccupied with acetaminophen-induced liver failure, it overlooked studies showing that regular users of acetaminophen may be doubling their risk of kidney cancer.165,167,171

Each year, almost 12,000 Americans die of kidney cancer.185 The incidence of kidney cancer in the US has risen 126% since the 1950s,185 a jump that may be tied to the growing use of drugs containing phenacetin or acetaminophen.

Phenacetin is a painkiller that was banned because it causes severe kidney toxicity.186-191 Acetaminophen is the major metabolite of phenacetin, which means that some of the destructive properties exhibited by phenacetin could have been caused by its breakdown to acetaminophen in the body. So while phenacetin was withdrawn because too many people’s kidneys were shutting down, the FDA had no problem letting the major metabolite of phenacetin (i.e., acetaminophen) be freely marketed without any consumer warning whatsoever. If acetaminophen is responsible for even a small percentage of the overall kidney cancer cases, this drug may have already killed tens of thousands of Americans.

Because acetaminophen generates damaging free radicals throughout the body, it may very well increase the risk of many age-related diseases. In fact, scientists can consistently induce cataracts in the eyes of laboratory animals by giving them acetaminophen. They consider acetaminophen a “cataractogenic agent.” Interestingly, if antioxidants are provided to the animals, the cataract-inducing effects of acetaminophen are often completely neutralized.192-197

One of Life Extension’s medical advisors long ago advocated that acetaminophen products should include the antioxidant N-acetylcysteine to help neutralize destructive free radicals. When a person acutely overdoses on acetaminophen, the standard medical therapy is to administer N-acetylcysteine over a period of weeks. Unfortunately, the FDA bans the combination of an over-the-counter drug (acetaminophen) with a dietary supplement (N-acetylcysteine), so it is “illegal” to make a safe acetaminophen drug.

To alert as many people as possible to the risks of acetaminophen poisoning and its antidotes, we included a chapter on analgesic toxicity in all four editions of our Disease Prevention and Treatment reference book.

The preceding reprint of a recent New York Times article articulates exactly what Life Extension has been saying since 1992 about the hepatotoxic dangers of acetaminophen. The article was originally published on November 29, 2005.

1. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003 Aug 7;349(6):523-34.

2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.

3. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13.

4. van Baal WM, Kenemans P, van der Mooren MJ, et al. Increased C-reactive protein levels during short-term hormone replacement therapy in healthy postmenopausal women. Thromb Haemost. 1999 Jun;81(6):925-8.

5. Vongpatanasin W, Tuncel M, Wang Z, et al. 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.

6. Available at: http://www.pdrhealth.com/ drug_info/rxdrugprofiles/drugs/pre1347.htm. Accessed January 18, 2006.

7. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-84.

8. 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.

9. Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68.

10. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62.

11. Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2663-72.

12. Lee S, Kolonel L, Wilkens L, et al. Postmenopausal hormone therapy and breast cancer risk: The multiethnic cohort. Int J Cancer. 2006 Mar 1;118(5):1285-91.

13. Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomized comparison: trial stopped. Lancet. 2004 Feb 7;363(9407):453-5.

14. Mueck AO, Seeger H, Wallwiener D. Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition. Climacteric. 2003 Sep;6(3):221-7.

15. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003 Jun 25;289(24):3243-53.

16. Lacey JV, Jr., Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002 Jul 17;288(3):334-41.

17. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control. 2002 Nov;13(9):847-54.

18. Gajdos C, Tartter PI, Babinszki A. Breast cancer diagnosed during hormone replacement therapy. Obstet Gynecol. 2000 Apr;95(4):513-8.

19. Chen Y, Liu X, Pisha E, et al. A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. Chem Res Toxicol. 2000 May;13(5):342-50.

20. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000 Jan 26; 283(4):485-91.

21. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000 Feb 16;92(4):328-32.

22. Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control. 1999 Aug;10(4):253-60.

23. Magnusson C, Baron JA, Correia N, et al. Breast-cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy. Int J Cancer. 1999 May 5;81(3):339-44.

24. Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol Biostat. 1999;4(3):191-210.

25. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst. 1999 Jul 7;91(13):1131-7.

26. Rodriguez C, Calle EE, Coates RJ, et al. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol. 1995 May 1;141(9):828-35.

27. Colditz GA, Stampfer MJ, Willett WC, et al. Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA. 1990 Nov 28;264(20):2648-53.

28. Hoover R, Gray LA, Sr., Fraumeni JF, Jr. Stilboestrol (diethylstilbestrol) and the risk of ovarian cancer. Lancet. 1977 Sep 10;2(8037):533-4.

29. Jo EH, Kim SH, Ra JC, et al. Chemopreventive properties of the ethanol extract of chinese licorice (Glycyrrhiza uralensis) root: induction of apoptosis and G1 cell cycle arrest in MCF-7 human breast cancer cells. Cancer Lett. 2005 Dec 18;230(2):239-47.

30. Touillaud MS, Pillow PC, Jakovljevic J, et al. Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutr Cancer. 2005;51(2):162-9.

31. Basly JP, Lavier MC. Dietary phytoestrogens: potential selective estrogen enzyme modulators? Planta Med. 2005 Apr;71(4):287-94.

32. Waite KA, Sinden MR, Eng C. Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet. 2005 Jun 1;14(11):1457-63.

33. Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res. 2005 Feb 1;65(3):879-86.

34. Linseisen J, Piller R, Hermann S, Chang-Claude J. Dietary phytoestrogen intake and premenopausal breast cancer risk in a German case-control study. Int J Cancer. 2004 Jun 10;110(2):284-90.

35. Brandt B, Hermann S, Straif K, et al. 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.

36. Annie S, Prabhu RG, Malini S. Activity of Wedelia calendulacea Less. in post-menopausal osteoporosis. Phytomedicine. 2006 Jan;13(1-2):43-8.

37. Effenberger KE, Johnsen SA, Monroe DG, Spelsberg TC, Westendorf JJ. Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens. J Steroid Biochem Mol Biol. 2005 Sep;96(5):387-99.

38. Roudsari AH, Tahbaz F, Hossein-Nezhad A, et al. Assessment of soy phytoestrogens’ effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial. Nutr J. 2005 Oct 29;430.

39. Lee YB, Lee HJ, Kim KS, et al. Evaluation of the preventive effect of isoflavone extract on bone loss in ovariectomized rats. Biosci Biotechnol Biochem. 2004 May;68(5):1040-5.

40. Nikander E, Metsa-Heikkila M, Ylikorkala O, Tiitinen A. Effects of phytoestrogens on bone turnover in postmenopausal women with a history of breast cancer. J Clin Endocrinol Metab. 2004 Mar;89(3):1207-12.

41. Fujioka M, Uehara M, Wu J, et al. Equol, a metabolite of daidzein, inhibits bone loss in ovariectomized mice. J Nutr. 2004 Oct;134(10):2623-7.

42. Xu HS, Dai SL, Sun RY. Cardiovascular effects of phytoestrogens. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005 Apr;27(2):258-61.

43. Altavilla D, Crisafulli A, Marini H, et al. Cardiovascular effects of the phytoestrogen genistein. Curr Med Chem Cardiovasc Hematol Agents. 2004 Apr;2(2):179-86.

44. Hintz KK, Ren J. Phytoestrogenic isoflavones daidzein and genistein reduce glucose-toxicity-induced cardiac contractile dysfunction in ventricular myocytes. Endocr Res. 2004 May;30(2):215-23.

45. Gardner JD, Brower GL, Janicki JS. Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats. J Appl Physiol. 2005 Oct;99(4):1378-83.

46. Schabath MB, Hernandez LM, Wu X, Pillow PC, Spitz MR. Dietary phytoestrogens and lung cancer risk. JAMA. 2005 Sep 28;294(12):1493-504.

47. Available at: http://www.cnn.com/2005/ HEALTH/conditions/08/10/lung.cancer.reeve.ap/. Accessed January 18, 2006.

48. Hecht SS, Carmella SG, Kenney PM, et al. 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 Biomarkers Prev. 2004 Jun;13(6):997-1004.

49. Lian F, Li Y, Bhuiyan M, Sarkar FH. p53-independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer. 1999;33(2):125-31.

50. Sun AS, Yeh HC, Wang LH, et al. Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients. Nutr Cancer. 2001;39(1):85-95.

51. dos SS, I, Mangtani P, McCormack V, et al. Phyto-oestrogen intake and breast cancer risk in South Asian women in England: findings from a population-based case-control study. Cancer Causes Control. 2004 Oct;15(8):805-18.

52. Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S. Soy, isoflavones, and breast cancer risk in Japan. J Natl Cancer Inst. 2003 Jun 18;95(12):906-13.

53. Yamamoto S, Sobue T, Sasaki S, et al. Validity and reproducibility of a self-administered food-frequency questionnaire to assess isoflavone intake in a Japanese population in comparison with dietary records and blood and urine isoflavones. J Nutr. 2001 Oct;131(10):2741-7.

54. Hirose K, Tajima K, Hamajima N, et al. A large-scale, hospital-based case-control study of risk factors of breast cancer according to menopausal status. Jpn J Cancer Res. 1995 Feb;86(2):146-54.

55. Sonoda T, Nagata Y, Mori M, et al. A case-control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet. Cancer Sci. 2004 Mar;95(3):238-42.

56. Ozasa K, Nakao M, Watanabe Y, et al. Serum phytoestrogens and prostate cancer risk in a nested case-control study among Japanese men. Cancer Sci. 2004 Jan;95(1):65-71.

57. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. 1998 Dec;9(6):553-7.

58. Horn-Ross PL, John EM, Canchola AJ, Stewart SL, Lee MM. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 2003 Aug 6;95(15):1158-64.

59. Xu WH, Zheng W, Xiang YB, et al. Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ. 2004 May 29;328(7451):1285.

60. Dai S, Duan J, Lu Y, et al. Phytoestrogen alpha-zearalanol inhibits atherogenesis and improves lipid profile in ovariectomized cholesterol-fed rabbits. Endocrine. 2004 Nov;25(2):121-9.

61. Dai S, Duan J, Lu Y, et al. Alpha-Zearalanol, a phytoestrogen for cardiovascular therapy. Endocrine. 2004 Nov;25(2):117-9.

62. Altavilla D, Saitta A, Galeano M, et al. The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats. Lab Invest. 2001 Feb;81(2):125-32.

63. Ji ES, Yue H, Wu YM, He RR. Effects of phytoestrogen genistein on myocardial ischemia/reperfusion injury and apoptosis in rabbits. Acta Pharmacol Sin. 2004 Mar;25(3):306-12.

64. van der Schouw YT, Pijpe A, Lebrun CE, et al. Higher usual dietary intake of phyto-estrogens is associated with lower aortic stiffness in postmenopausal women. Arterioscler Thromb Vasc Biol. 2002 Aug 1;22(8):1316-22.

65. Cassidy A. Potential risks and benefits of phytoestrogen-rich diets. Int J Vitam Nutr Res. 2003 Mar;73(2):120-6.

66. Holzbeierlein JM, McIntosh J, Thrasher JB. The role of soy phytoestrogens in prostate cancer. Curr Opin Urol. 2005 Jan;15(1):17-22.

67. Bhathena SJ, Velasquez MT. Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr. 2002 Dec;76(6):1191-201.

68. Anthony MS, Clarkson TB, Williams JK. Effects of soy isoflavones on atherosclerosis: potential mechanisms. Am J Clin Nutr. 1998 Dec;68(6 Suppl):1390S-3S.

69. Branca F, Lorenzetti S. Health effects of phytoestrogens. Forum Nutr. 2005;(57):100-11.

70. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol. 2000 May;35(6):1403-10.

71. Adlercreutz H, Heinonen SM, Penalvo-Garcia J. Phytoestrogens, cancer and coronary heart disease. Biofactors. 2004;22(1-4):229-36.

72. McCann MJ, Gill CI, McGlynn H, Rowland IR. Role of Mammalian lignans in the prevention and treatment of prostate cancer. Nutr Cancer. 2005;52(1):1-14.

73. Beck V, Rohr U, Jungbauer A. Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol. 2005 Apr;94(5):499-518.

74. Vaya J, Tamir S. The relation between the chemical structure of flavonoids and their estrogen-like activities. Curr Med Chem. 2004 May;11(10):1333-43.

75. Mackey R, Eden J. Phytoestrogens and the menopause. Climacteric. 1998 Dec;1(4):302-8.

76. Barnes S. Soy isoflavones—phytoestrogens and what else? J Nutr. 2004 May;134(5):1225S-8S.

77. Limer JL, Speirs V. Phyto-oestrogens and breast cancer chemoprevention. Breast Cancer Res. 2004;6(3):119-27.

78. Ariyo AA, Villablanca AC. Estrogens and lipids. Can HRT designer estrogens, and phytoestrogens reduce cardiovascular risk markers after menopause? Postgrad Med. 2002 Jan;111(1):23-30.

79. Valachovicova T, Slivova V, Sliva D. Cellular and physiological effects of soy flavonoids. Mini Rev Med Chem. 2004 Oct;4(8):881-7.

80. Lukaczer D, Darland G, Tripp M, et al. Clinical effects of a proprietary combination isoflavone nutritional supplement in menopausal women: a pilot trial. Altern Ther Health Med. 2005 Sep;11(5):60-5.

81. Powles T. Isoflavones and women’s health. Breast Cancer Res. 2004;6(3):140-2.

82. Viereck V, Emons G, Wuttke W. Black cohosh: just another phytoestrogen? Trends Endocrinol Metab. 2005 Jul;16(5):214-21.

83. Available at: http://www.lifeextension.com/magazine/mag2003/jul2003_report_i3c_01.html. Accessed January 18, 2006.

84. He YH, Friesen MD, Ruch RJ, Schut HA. Indole-3-carbinol as a chemopreventive agent in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis: inhibition of PhIP-DNA adduct formation, acceleration of PhIP metabolism, and induction of cytochrome P450 in female F344 rats. Food Chem Toxicol. 2000 Jan;38(1):15-23.

85. Arif JM, Gairola CG, Kelloff GJ, Lubet RA, Gupta RC. Inhibition of cigarette smoke-related DNA adducts in rat tissues by indole-3-carbinol. Mutat Res. 2000 Jul 20;452(1):11-8.

86. Bell MC, Crowley-Nowick P, Bradlow HL, et al. Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol. 2000 Aug;78(2):123-9.

87. Rahman KM, Aranha O, Glazyrin A, Chinni SR, Sarkar FH. Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. Oncogene. 2000 Nov 23;19(50):5764-71.

88. Meng Q, Qi M, Chen DZ, et al. Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes. J Mol Med. 2000;78(3):155-65.

89. Jin L, Qi M, Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 1999 Aug 15;59(16):3991-7.

90. Cover C, Hsieh S, Cram E, et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res. 1999 Mar15;59(6):1244-51.

91. Cover CM, Hsieh SJ, Tran SH, et al. Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem. 1998 Feb 13;273(7):3838-47.

92. Manson MM, Hudson EA, Ball HW, et al. Chemoprevention of aflatoxin B1-induced carcinogenesis by indole-3-carbinol in rat liver—predicting the outcome using early biomarkers. Carcinogenesis. 1998 Oct;19(10):1829-36.

93. Grubbs CJ, Steele VE, Casebolt T, et al. Chemoprevention of chemically induced mammary carcinogenesis by indole-3-carbinol. Anticancer Res. 1995 May;15(3):709-16.

94. Tiwari RK, Guo L, Bradlow HL, Telang NT, Osborne MP. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. J Natl Cancer Inst. 1994 Jan 19;86(2):126-31.

95. Bradlow HL, Michnovicz J, Telang NT, Osborne MP. Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis. 1991 Sep;12(9):1571-4.

96. Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer. 1991;16(1):59-66.

97. Shertzer HG, Berger ML, Tabor MW. Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol. Biochem Pharmacol. 1988 Jan 15;37(2):333-8.

98. Kang JH, Park YH, Choi SW, Yang EK, Lee WJ. Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells. Exp Mol Med. 2003 Dec 31;35(6):467-74.

99. Tsan MF, White JE, Maheshwari JG, Chikkappa G. Anti-leukemia effect of resveratrol. Leuk Lymphoma. 2002 May;43(5):983-7.

100. Asou H, Koshizuka K, Kyo T, et al. Resveratrol, a natural product derived from grapes, is a new inducer of differentiation in human myeloid leukemias. Int J Hematol. 2002 Jun;75(5):528-33.

101. Kimura Y, Okuda H. Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice. J Nutr. 2001 Jun;131(6):1844-9.

102. Kozuki Y, Miura Y, Yagasaki K. Resveratrol suppresses hepatoma cell invasion independently of its anti-proliferative action. Cancer Lett. 2001 Jun 26;167(2):151-6.

103. Nakagawa H, Kiyozuka Y, Uemura Y, et al. Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol. 2001 Apr;127(4):258-64.

104. Bernhard D, Tinhofer I, Tonko M, et al. Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells. Cell Death Differ. 2000 Sep;7(9):834-42.

105. Szende B, Tyihak E, Kiraly-Veghely Z. Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures. Exp Mol Med. 2000 Jun 30;32(2):88-92.

106. Tessitore L, Davit A, Sarotto I, Caderni G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis. 2000 Aug;21(8):1619-22.

107. Jang M, Pezzuto JM. Cancer chemopreventive activity of resveratrol. Drugs Exp Clin Res. 1999;25(2-3):65-77.

108. Clement MV, Hirpara JL, Chawdhury SH, Pervaiz S. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood. 1998 Aug 1;92(3):996-1002.

109. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001 Dec;74(6):714-22.

110. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23.

111. Smigel K. Vitamin E reduces prostate cancer rates in Finnish trial: U.S. considers follow-up. J Natl Cancer Inst. 1998 Mar 18;90(6):416-7.

112. Nomura AM, Ziegler RG, Stemmermann GN, Chyou PH, Craft NE. Serum micronutrients and upper aerodigestive tract cancer. Cancer Epidemiol Biomarkers Prev. 1997 Jun;6(6):407-12.

113. Christen S, Woodall AA, Shigenaga MK, et al. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci USA. 1997 Apr 1;94(7):3217-22.

114. Sanchez-Barcelo EJ, Cos S, Fernandez R, Mediavilla MD. Melatonin and mammary cancer: a short review. Endocr Relat Cancer. 2003 Jun;10(2):153-9.

115. Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002 Feb;2(2):113-32.

116. Ram PT, Yuan L, Dai J, et al. Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone, melatonin. J Pineal Res. 2000 May;28(4):210-8.

117. Cos S, Fernandez R, Guezmes A, Sanchez-Barcelo EJ. Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells. Cancer Res. 1998 Oct 1;58(19):4383-90.

118. Lissoni P, Brivio F, Brivio O, et al. Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeost Agents. 1995 Jan;9(1):31-3.

119. Lissoni P, Barni S, Ardizzoia A, et al. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer. 1994 Feb 1;73(3):699-701.

120. Oosthuizen JM, Bornman MS, Barnard HC, et al. Melatonin and steroid-dependent carcinomas. Andrologia. 1989 Sep;21(5):429-31.

121. 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.

122. 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.

123. Diel P, Geis RB, Caldarelli A, et al. The differential ability of the phytoestrogen genistein and of estradiol to induce uterine weight and proliferation in the rat is associated with a substance specific modulation of uterine gene expression. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):21-32.

124. Wood CE, Register TC, Anthony MS, Kock ND, Cline JM. Breast and uterine effects of soy isoflavones and conjugated equine estrogens in postmenopausal female monkeys. J Clin Endocrinol Metab. 2004 Jul;89(7):3462-8.

125. 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.

126. Li Y, Sarkar FH. Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett. 2002 Dec 5;186(2):157-64.

127. Khoshyomn S, Nathan D, Manske GC, Osler TM, Penar PL. Synergistic effect of genistein and BCNU on growth inhibition and cytotoxicity of glioblastoma cells. J Neurooncol. 2002 May;57(3):193-200.

128. Bhatia N, Agarwal R. Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells. Prostate. 2001 Feb 1;46(2):98-107.

129. Guo TL, McCay JA, Zhang LX, et al. Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice. J Nutr. 2001 Dec;131(12):3251-8.

130. Wietrzyk J, Boratynski J, Grynkiewicz G, et al. Antiangiogenic and antitumour effects in vivo of genistein applied alone or combined with cyclophosphamide. Anticancer Res. 2001 Nov;21(6A):3893-6.

131. Suthar AC, Banavalikar MM, Biyani MK. Pharmacological activities of Genistein, an isoflavone from soy (Glycine max): part I—anti-cancer activity. Indian J Exp Biol. 2001 Jun;39(6):511-9.

132. Sakamoto K. Synergistic effects of thearubigin and genistein on human prostate tumor cell (PC-3) growth via cell cycle arrest. Cancer Lett. 2000 Apr 3;151(1):103-9.

133. Shen JC, Klein RD, Wei Q, et al. Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. Mol Carcinog. 2000 Oct;29(2):92-102.

134. Elattar TM, Virji AS. The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro. Anticancer Res. 2000 May;20(3A):1733-8.

135. Lu LJ, Cree M, Josyula S, et al. 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):1299-305.

136. 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.

137. Dalu A, Haskell JF, Coward L, Lamartiniere CA. Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate. Prostate. 1998 Sep 15;37(1):36-43.

138. Geller J, Sionit L, Partido C, et al. Genistein inhibits the growth of human-patient BPH and prostate cancer in histoculture. Prostate. 1998 Feb 1;34(2):75-9.

139. Shao ZM, Wu J, Shen ZZ, Barsky SH. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res. 1998 Nov 1;58(21):4851-7.

140. Theodorescu D, Laderoute KR, Calaoagan JM, Guilding KM. Inhibition of human bladder cancer cell motility by genistein is dependent on epidermal growth factor receptor but not p21ras gene expression. Int J Cancer. 1998 Dec 9;78(6):775-82.

141. Record IR, Broadbent JL, King RA, et al. Genistein inhibits growth of B16 melanoma cells in vivo and in vitro and promotes differentiation in vitro. Int J Cancer. 1997 Sep 4;72(5):860-4.

142. 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.

143. Barnes S. Effect of genistein on in vitro and in vivo models of cancer. J Nutr. 1995 Mar;125(3 Suppl):777S-83S.

144. Versantvoort CH, Broxterman HJ, Lankelma J, Feller N, Pinedo HM. Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells. Biochem Pharmacol. 1994 Sep 15;48(6):1129-36.

145. Haber D. Roads leading to breast cancer. N Engl J Med. 2000 Nov 23;343(21):1566-8.

146. Strauss B, Turkington E, Wang J, Sagher D. Mutagenic consequences of the alteration of DNA by chemicals and radiation. Adv Exp Med Biol. 1991;283:211-23.

147. Olsen A, Knudsen KE, Thomsen BL, et al. Plasma enterolactone and breast cancer incidence by estrogen receptor status. Cancer Epidemiol Biomarkers Prev. 2004 Dec;13(12):2084-9.

148. Power KA, Saarinen NM, Chen JM, Thompson LU. Mammalian lignans enterolactone and enterodiol, alone and in combination with the isoflavone genistein, do not promote the growth of MCF-7 xenografts in ovariectomized athymic nude mice. Int J Cancer. 2006 Mar 1;118(5):1316-20.

149. Brooks JD, Thompson LU. Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells. J Steroid Biochem Mol Biol. 2005 Apr;94(5):461-7.

150. Boccardo F, Puntoni M, Guglielmini P, Rubagotti A. Enterolactone as a risk factor for breast cancer: A review of the published evidence. Clin Chim Acta. 2005 Sep 13.

151. Nagel G, Mack U, von FD, Linseisen J. Dietary phytoestrogen intake and mammographic density—results of a pilot study. Eur J Med Res. 2005 Sep 12;10(9):389-94.

152. Hussain M, Banerjee M, Sarkar FH, et al. Soy isoflavones in the treatment of prostate cancer. Nutr Cancer. 2003;47(2):111-7.

153. Wei H, Saladi R, Lu Y, et al. Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutr. 2003 Nov;133(11 Suppl 1):3811S-9S.

154. Lund TD, Munson DJ, Haldy ME, et al. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod. 2004 Apr;70(4):1188-95.

155. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72.

156. Available at: http://www.fda.gov/bbs/topics/NEWS/2004/NEW01008.htm. Accessed February 27, 2004.

157. Available at: http://www.fda.gov/ohrms/ dockets/ac/02/agenda/3882A_Draft.doc. Accessed February 27, 2004.

158. Available at: http://www.fdanews.com/ 1_1/dailynews/7334-1.html. Accessed February 27, 2004.

159. Anand BS, Romero JJ, Sanduja SK, Lichtenberger LM. Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects. Am J Gastroenterol. 1999 Jul; 94(7):1818-22.

160. Blakely P, McDonald BR. Acute renal failure due to acetaminophen ingestion: a case report and review of the literature. J Am Soc Nephrol. 1995 Jul;6(1):48-53.

161. Bonkovsky HL, Kane RE, Jones DP, Galinsky RE, Banner B. Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency. Hepatology. 1994 May;19(5):1141-8.

162. Clemmesen JO, Ott P, Dalhoff KP, Astrup LB, TageJensen U, Poulsen HE. Recommendations for treatment of paracetamol poisoning. Ugeskr Laegr. 1996 Nov 25; 158(48):6892-5.

163. Conti M, Malandrino S, Magistretti MJ. Protective activity of silipide on liver damage in rodents. Jpn J Pharmacol. 1992 Dec;60(4):315-21.

164. DeLeve LD, Kaplowitz N. Glutathione metabolism and its role in hepatotoxicity. Pharmacol Ther. 1991 Dec;52(3):287-305.

165. Derby LE, Jick H. Acetaminophen and renal and bladder cancer. Epidemiology. 1996 Jul;7(4):358-62.

166. Dunjic BS, Axelson J, Ar’Rajab A, Larsson K, Bengmark S. Gastroprotective capability of exogenous phosphatidylcholine in experimentally induced chronic gastric ulcers in rats. Scand J Gastroenterol. 1993 Jan;28(1):89-94.

167. Gago-Dominguez M., Yuan JM, Castelao JE, Ross RK, Yu MC. Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer. 1999 Oct;81(3):542-8.

168. Graudins A, Aaron CK, Linden CH. Overdose of extended-release acetaminophen. N Engl J Med. 1995 Jul 20;333(3):196.

169. Jaeschke H, Werner C, Wendel A. Disposition and hepatoprotection by phosphatidyl choline liposomes in mouse liver. Chem Biol Interact. 1987;64(1-2):127-37.

170. Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late acetaminophen poisoning: a critical review. J Toxicol Clin Toxicol. 1998;36(4):277-85.

171. Kaye JA, Myers MW, Jick H. Acetaminophen and the risk of renal and bladder cancer in the general practice research database. Epidemiology. 2001 Nov;12(6):690-4.

172. Kind B, Krahenbuhl S, Wyss PA, Meier-Abt PJ. Clinical-toxicological case (1). Dosage of N-acetylcysteine in acute paracetamol poisoning. Schweiz Rundsch Med Prax. 1996 Aug 2; 85(31-32):935-8.

173. Lieber CS. Role of oxidative stress and antioxidant therapy in alcoholic and non-alcoholic liver diseases. Adv Pharmacol. 1997;38:601-28.

174. Lieber CS. Alcohol: its metabolism and interaction with nutrients. Annu Rev Nutr. 2000;20:395-430.

175. McLaughlin JK, Blot WJ, Mehl ES, Fraumeni JF Jr. Relation of analgesic use to renal cancer: population-based findings. Natl Cancer Inst Monogr. 1985 Dec;69:217-22.

176. Mitchell T, Needham A. Over-the-counter drug is treatment for Alzheimer’s. Life Extension. November, 2000:50-5.

177. Price LM, Poklis A, Johnson DE. Fatal acetaminophen poisoning with evidence of subendocardial necrosis of the heart. J Forensic Sci. 1991 May;36(3):930-5.

178. Richie JP Jr, Lang CA, Chen TS. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Biochem Pharmacol. 1992 Jul 7;44(1):129-35.

179. Siegers CP, Moller-Hartmann W. Cholestyramine as an antidote against paracetamol-induced hepato- and nephrotoxicity in the rat. Toxicol Lett. 1989 May;47(2):179-84.

180. Uhlig S, Wendel A. Glutathione enhancement in various mouse organs and protection by glutathione isopropyl ester against liver injury. Biochem Pharmacol. 1990 Jun 15;39(12):1877-81.

181. Werner C, Wendel A. Hepatic uptake and antihepatotoxic properties of vitamin E and liposomes in the mouse. Chem Biol Interact. 1990;75(1):83-92.

182. Zhao J, Agarwal R. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis. 1999 Nov;20(11):2101-8.

183. Available at: http://www.fda.gov/cder/ drug/analgesics/letter.htm. Accessed February 27, 2004.

184. Available at: http://www.fda.gov/cder/ drug/ analgesics/SciencePaper.htm. Accessed February 27, 2004.

185. Available at: http://www.kidney-cancer-symptoms.com. Accessed February 27, 2004.

186. Piper JM, Tonascia J, Matanoski GM. Heavy phenacetin use and bladder cancer in women aged 20 to 49 years. N Engl J Med. 1985 Aug 1;313(5):292-5.

187. Linet MS, Chow WH, McLaughlin JK, et al. Analgesics and cancers of the renal pelvis and ureter. Int J Cancer. 1995 Jul 4;62(1):15-8.

188. McCredie M, Stewart JH, Day NE. Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis. Int J Cancer. 1993 Jan 21;53(2):245-9.

189. Brunner FP, Selwood NH. End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee. Nephrol Dial Transplant. 1994;9(10):1371-6.

190. Stewart JH, Hobbs JB, McCredie MR. Morphologic evidence that analgesic-induced kidney pathology contributes to the progression of tumors of the renal pelvis. Cancer. 1999 Oct 15;86(8):1576-82.

191. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin. Renal morbidity and mortality (1968-1979). N Engl J Med. 1983 Feb 17;308(7):357-62.

192. Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Maintenance of hepatic glutathione homeostasis and prevention of acetaminophen-induced cataract in mice by L-cysteine prodrugs. Biochem Pharmacol. 1996 May 3;51(9):1111-6.

193. Rathbun WB, Holleschau AM, Cohen JF, Nagasawa HT. Prevention of acetamino- phen- and naphthalene-induced cataract and glutathione loss by CySSME. Invest Ophthalmol Vis Sci. 1996 Apr;37(5):923-9.

194. Nagasawa HT, Shoeman DW, Cohen JF, Rathbun WB. Protection against acetamin- ophen-induced hepatotoxicity by L- CySSME and its N-acetyl and ethyl ester derivatives. J Biochem Toxicol. 1996;11(6):289-95.

195. Zhao C, Shichi H. Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine. J Ocul Pharmacol Ther. 1998 Aug;14(4):345-55.

196. Qian W, Shichi H. Cataract formation by a semiquinone metabolite of acetaminophen in mice: possible involvement of Ca(2+)and calpain activation. Exp Eye Res. 2000 Dec;71(6):567-74.

197. Qian W, Shichi H. Acetaminophen produces cataract in DBA2 mice by Ah receptor-independent induction of CYP1A2. J Ocul Pharmacol Ther. 2000 Aug;16(4):337-44.