If you’ve not already been alarmed by the push for statins as primary heart disease prevention you will want to know that in 2006, 1.3 million coronary angioplasty procedures were done in the U.S., at a cost of $48,399.00 and 448,000 coronary bypass operations at a cost of $99,743.00. That’s a total of over 104 billion dollars. For those two procedures alone, we spent more than 100 billion dollars in 2006. If these procedures accomplished as much as they cost, that would be one thing, but even the New England Journal of Medicine reported in 2007 that angioplasties and stents do not prolong life or prevent heart attacks in stable patients; stable patients are 95% of those who undergo those procedures. And…. coronary bypass surgery sadly prolongs life in less than 3% of patients. We have good scientific evidence that diet and lifestyle changes can prevent at least 90% of all heart disease. 90%!!!!!! In yet another recent study proving this point, an intervention diet of either low-fat or Mediterranean diet significantly improved cardiovascular event free survival in those who had a previous heart attack.[1]

The well known Lyon Diet Heart Study also demonstrated a survival advantage with the Mediterranean diet.[2]

For both primary and secondary heart disease prevention, we have to step up our game in helping our patients “get religion” about rigorously changing their eating habits, losing weight, exercising a minimum of 30 minutes every day (and for overweight 40 and over women, likely 60 + minutes daily), and of course stopping smoking.

In addition to using nutritional and botanical supplementation to address any lipid or hypertension issues, a diverse approach attending to arterial health and inflammation deserves our attention as well. While questioning statins, we might also want to question our own use of nutraceuticals in treating hyperlipidemia with items such as soluble fibers, soy, red yeast rice, niacin, phytosterols, pantethine, tocotrienols, resveratrol, policosanol, gugulipids or garlic. I have as of yet not abandoned this thinking of improving lipid profiles, but a broader perspective is in order. While of course attending to normalizing blood pressure, (magnesium, potassium, bonito protein, marine omega 3 fatty acids, vitamin D, lycopene, pycnogenol, hawthorne, L-arginine, carnitine, NAC and more) I have also expanded my attention to arterial health with attention to dilatation, anti-inflammation, reduction of LDL oxidation, platelet function and reducing vascular calcification.

I look more to combination ingredients and product formulations that approach cardiovascular health from the multi-mechanism perspective. While not an exhaustive list, items to consider beyond lipid therapies:

Dilatation: L-arginine, quercitin/flavonoids, vitamin C and E, magnesium, co-enzyme Q-10, taurine, garlic, soy

Anti-inflammation: marine omega 3 fatty acids, flax oil, isoquercitin, quercitin/rutin/ flavonoids, resveratrol

Reduce LDL oxidation: niacin, green tea, garlic, pantethine, resveratrol, policosanol, Co-enzyme Q-10

Anti-thrombotic: marine omega 3 fatty acids, garlic, pomegranate, nattokinase, ginger, resveratrol

Reduce vascular calcification: Vitamin K2, marine omega 3 fatty acids

More than 500,000 women die of cardiovascular-related causes annually in the U.S., with approximately 100,000 prematurely, before the age of 65. Starting at age 50, more women die of cardiovascular diseases than of any other condition and women younger than 55 who have a heart attack have a worse prognosis and higher incidence of heart attack-related death than do men of the same age who have a heart attack, as well as a greater chance of having another heart attack. Disability due to cardiovascular disease is also a major concern, especially in older women. And for African-American women, the risk of heart-related death is even greater- it is twice as high as for Caucasian women.

To be successful with our mission of preventing and treating heart disease, and helping women with the difficult challenges of weight loss and lifestyle changes, we must enhance patient education, expand strategies for motivation, improve and broaden plant/nutrient based supplementation prescribing, and continue wise and considered selective/judicious use of pharmaceutical/conventional interventions.

References

[2] De Lorgeril M, Salen P, Martin J, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779-785.

• enhance the individual’s internal defenses against the infection by providing immune support
• restore vaginal and bladder microflora, enhancing the flow of urine
• promote a proper pH
• prevent bacteria from adhering to the bladder epithelium

Increasing the urinary flow is easily accomplished by increasing the quantity of liquids. Water and herbal teas related to the treatment goals are the most logical choices. 64 ounces per day is the common recommendation.

No natural approach to cystitis would be complete without mention of cranberry. Women have used cranberry juice as a home remedy for decades. Several studies have shown that cranberries and cranberry juice are effective in women with active urinary tract infections. In one study, 16 ounces of cranberry juice daily was effective in 73% of individuals with an active infection.1 Cranberry has also been shown to reduce the ability of E. coli to adhere to the lining of the bladder and urethra. Many people still think that the action of cranberry juice is due to acidifying the urine. However, recent studies have shown that components in cranberry juice reduce the ability of E. coli to adhere to the lining of the bladder and urethra.

One of the most useful herbs for bladder infection is uva ursi (Arctostaphylos uva ursi), also known as bearberry or upland cranberry. The antiseptic, antibacterial and astringent activity of uva ursi is largely due to its arbutin content. Uva ursi is especially active against E. coli as well as having diuretic properties. Uva ursi has also been used with recurrent bladder infections and was very effective in a double-blind study of 57 women. After one year, five of twenty-seven women had a recurrence in the placebo group while none of thirty women had a recurrence in the uva ursi group. Pipsissewa, a Native remedy of the Pacific Northwest, is a traditional remedy for urinary infections. It’s mildly antimicrobial effects have been attributed to its arbutin content.

Oregon grape root is another useful herb in bladder infections due to its antimicrobial properties. Specifically, it has demonstrated antibacterial activity against E. Coli and Proteus species. Oregon grape root and Goldenseal are rich sources of one of the most significant plant based antibacterial active constituents, berberine. Berberine is effective against many bacteria and is also able to fight infections by inhibiting the bacteria from adhering to the host cell.

Other botanicals have been traditionally used for bladder infections with positive effect. The water-soluble mucilage herbs are known to be soothing to the irritated uroepithelium and reduce inflammation. These include corn silk for its soothing and cooling effect on the urinary tract; marshmallow root due to its content of mucilage, which can form a protective layer on the lining of the bladder; and even plantain leaf with its high percentage of mucilage and allantoin. Additional antimicrobial herbs for the bladder include bucchu, myrrh, propolis and juniper berry. Numerous immune stimulants may be helpful including echinacea, osha and wild indigo root. Bladder tonics stimulate the flow of blood and nutrients to the urinary tract and may be useful adjunct herbs. These include nettles leaves, goldenrod, kava kava and horsetail. Dandelion leaf, bucchu and parsley root have diuretic effects and increase the flow of urine to help flush the bacteria.

Probiotics, or “live micro-organisms that confer a health benefit for the host” for the prevention of urinary tract infections (UTIs) are useful in establishing and maintaining a proper bladder pH and enhancing a normal ecology of the vagina, urethra and bladder. Lactobacilli dominate the urogenital flora of healthy reproductive aged women. Several in vitro and in vivo studies support the therapeutic benefit of several strains of lactobacilli on the restoration of vaginal ecology and flora and the prevention of recurrent bladder infections. Lactobacillus rhamnosus and Lactobacillus fermentum appear to be the most effective.

References

• Prodromos P, Brusch C, Ceresia G. Cranberry Juice in the treatment of urinary tract infections. Southwest Med 1968; 47:17.
• Sternlief P. Cranberry Juice in renal disease. New Engl J Med 1963;268:57
• Moen D. Observations on the effectiveness of cranberry juice in urinary infections. Wisconsin Med J 1962;61:282.
• Ofek I, Goldhar J, et al. Anti-Escherichia coli adhesion activity of cranberry and blueberry juices. NEJM 1991; 324:1599
• Zafiri D, Ofek I, et al. Inhibitory activity of cranberry juice on adherence of type 1 and type P fimbriated Escherichia coli to eucaryotic cells. Antimicrob Agents Chemother 1989;33:92-98.
• Sobota A. Inhibition of bacterial adherence by cranberry juice: potential use for the treatment of urinary tract infections. J Urology 1984; 131:1013-1016.
• Ofek I, et al. Anti-escherichia activity of cranberry and blueberry juices. NEJM 1991; 324:1599.
• Larsson B, Jonasson A, Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: A Preliminary Report. Curr Ther Res 1993;53:441-443.
• Amin A, Subbaiah T, Abbasi K. Berberine Sulfate: Antimicrobial activity, bioassay, and mode of action. Can J Microbiol 1969;15:1067-1076.
• Johnson C, Johnson G, Poe C. Toxicity of alkaloids to certain bacteria. Acta Pharmacol Toxicol 1952;8:71-78.
• Hahn F, Ciak J. Berberine. Antibiotics 1976;3:577-588
• Falagas M, Betsi G, Tokas T, Athanasiou S. Probiotics for prevention of recurrent urinary tract infections in women. Drugs 2006;66(9):1253-1261.

Soybeans contain a class of compounds called phytoestrogens, comprising mostly genistein, daidzein and glycitein, all of which have a biochemical structure similar to 17 beta estradiol. The binding of isoflavones to estrogen receptors is preferential for the estrogen receptor beta and thus indicates that soy isoflavones act as selective estrogen modulators. Daidzein is similar in shape to a drug called Ipriflavone which is used in Europe to treat osteoporosis. In the U.S., Ipriflavone is available as a nutritional supplement.

Bone mineral density (BMD) is the gold standard for determining fracture risk due to nontraumatic events. Bone turnover is an independent predictor of fracture risk.

While the effects of soy on bone metabolism has been inconsistent, many positive studies do exist that suggest a role for soy in slowing bone turnover and bone density in women. Soy appears to have a pro estrogen effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in which soy replaced casein in the diet, compared to another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as was achieved with the estrogen treatment. Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen genistein in maintaining bone. These authors also reported that genistein suppresses the bone losing cells (osteoclasts), both in the test tube and in vivo. Arjmandi also did a double-blind, randomized, controlled trial using 40g of soy protein containing isoflavones over 3 months in postmenopausal women. Bone resorption was decreased, when compared to milk protein.

Several human studies have provided further insight and comfort in the possible role of soy in our bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55-90 mg of isoflavones for six months. The placebo group showed the lowest bone density and the greatest bone loss, while the estrogen group showed the highest bone density and the slowest bone loss. What was surprising was that the soybean diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip as well. Soybean seems to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soy did not show as great an ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging.

A study of the relation of soy isoflavone intake and bone mineral density was conducted within the Study of Women’s Health Across the Nation, a US cohort study of women aged 42-52 years. For African-American and Caucasian women, average intakes of genistein was too low to pursue analyses. For Chinese women, no association between genistein and bone mineral density was found. Pre-menopausal, but not peri-menopausal, Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. Mean spinal bone density of those women in the highest group was 7.7% greater than that of women in the lowest group. Bone density of the femoral neck was 12% greater in the highest intake group versus the lowest.

Other positive studies on soy and bone density also give some credence to the role of soy and bone health. In a study estimating the daily intakes of soy isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption, high consumption of soy products was associated with increased bone mass.

A very recent analysis of nine studies further increases our optimism about using soy to inhibit bone resorption. Nine studies with a total of 432 menopausal women were evaluated for meta-analysis. Amount of soy intake varied amongst the nine studies from 37 mg of isoflavones per day to 118 mg of isoflavones per day. Testing for urinary peptides (deoxypyridinoline) of bone turnover demonstrated that when all nine study results are combined, those who consumed isoflavones had a decrease in these biomarkers of -2.08 nmol/mmol when compared to those who did not consume isoflavones. In five of the studies, isolated soy protein was used, as a group, there was no significant effect on urinary deoxypyridinoline. In the current analysis, significant reduction in urinary deoxypyridinoline did not occur in those studies with isoflavones of less than 90 mg/day. In a review of the research in 2003, the author concluded that 90mg of isoflavones per day is required to achieve benefits on bone health.

In contrast to the positive studies, several clinical trials using a variety of soy protein isolate formulations found no clinically important effects of soy on bone metabolism and bone turnover markers. Further inconsistent research can be seen with several clinical trials using soy protein or isoflavones demonstrating a positive effect on BMD, while others have not had positive findings.

I mentioned variations in dosing, duration, soy formulations used, and different study populations as possible reasons for inconsistent results on the effects of soy isoflavones on bone turnover and bone density. But, another significant consideration may be due to how the isoflavones are metabolized in the gut. In the recent study mentioned about analyzing nine studies 10 the significant effects on urinary peptides occurred in Asian women but not Caucasian women. This may be due to the conversion of isoflavones into its active metabolite equol in intestinal flora, and that only one-third of Caucasian women can metabolize isoflavones into equol, whereas more than half of Asian women possess this ability.

Soy isoflavones may also have more of an effect in post-menopausal women than in pre or perimenopausal women. In one study, 53.3 mg of isoflavones per day was associated with an increase in bone density in postmenopausal women, but not pre-menopausal women.

An area of soy foods that may be overlooked, is the amount of calcium in some soy foods. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much or more calcium than a serving of dairy products.

With the inconsistent research, it is difficult to draw confident conclusions about the role of soy in bone health. My clinical advice is to increase soy foods as part of a regular diet in prevention strategies for all pre, peri and postmenopausal women. For all women who have significant risk factors for osteoporosis, I would in addition, recommend soy supplementation so that their total daily soy isoflavone intake would deliver approximately 90 mg of soy isoflavones per day. For treatment of peri and postmenopausal women who already have osteoporosis, I would not consider soy an adequate treatment alone. In addition to the 90 mg per day of soy isoflavones and typical supplementation including calcium, vitamin D and other potential nutrients (K, boron, magnesium, manganese, and more), dietary and exercise advice, for these women who already have osteoporosis, I am in favor of proven conventional therapies to reduce fracture risk.

References

• Weaver C, Cheong J. Soy isoflavones and bone health: the relationship is still unclear. J Nutr 2005; 135:1243-1247.
• Setchell K. Soy isoflavones-benefits and risk from nature’s selective estrogen receptor modulators (SERMS). J Am Coll Nutr 2001; 20: 354S-362S.
• Garnero P, Hausherr E, Chapuy M, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J Bone Miner Res 1996; 11:1531-1538.
• Arjmandi B, Alekel L, Hollis B, Amin D, Stacwicz-Sapuntzakis M, Guo , Kukreja S. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr 1996;126:161-167.
• Blair H, Jordan S, Peterson T, Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J cell Biochem. 1996;61:629-637.
• Arjmandi B, Khalil D, Smith B, et al. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab 2003; 88: 1048-1054.
• Erdman J, Stillman R, Lee K, Potter S. Short-term effects of soybean isoflavones on bone in postmenopausal women. Program and Abstract Book, Second International symposium on the Role of Soy in Preventing and Treating Chronic Disease. Brussels, Belgium, 1996.
• Greendale G, FitzGerald G, Huang M, et al. Dietary soy isoflavones and bone mineral density: Results from the study of women’s health across the nation. Amer J Epidemiology 2002;155(8):746-754.
• Somekawa Y, Chiguchi M, Ishibashi T, Takeshi A. Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet Gynecol 2001;97:109-115.
• Ma D-F, Qin L-Q, Want P-Y, Katoh R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. European J of Clinical Nutrition 2008; 62:155-161.
• Branca F. Dietary phyto-oestrogens and bone health. Proc Nutr Soc 2003; 62: 877-887.
• Wangen K, Duncan A, merz-Demlow B, et al. Effects of soy isoflavoens on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000; 85:3043-3048.
• Knight D, Howes J, Eden J, Howes L. Effects of menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric 2001; 4:13-18.
• Dalais F, Ebeling P, Kotsopoulos D, McGrath B, Teede H. The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women. Clin Endocrinol 2003; 58:704-709.
• Potter S, Baum J, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998; 68:1375S-1379S.
• Alekel D, Germain A, Peterson C, et al. Isoflavone-rich soy protein attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr 2000; 72:844-852.
• Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo controlled study. J Bone Miner Res 2002; 17:1904-1912.
• Chen Y, Ho S, Lam S, Ho S, Woo J. Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4740-4747.
• Lydeking-Olsen E, Beck-Jensen J, Setchell K, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss: a 2 year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.
• Gallagher J, Satpathy R, Rafferty K, Haynatzka V. The effect of soy protein on bone metabolism. Menopause 2004; 11:290-298.
• Kreijkamp-Kaspers S, Kok L, et al. Effects of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women. JAMA 2004; 292:65-74.
• MeiJ, Yeung S, Kung A. High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 2001; 86:5217-5221

Lappe J, et al. Â Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Â Am J Clin Nut 2007; une 85: 1586-1591

Lin J et al.  Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 2007, May 28; 167:1050-1059.

Comparing the incidence rates in 2001 with the rates in 2004, but not including this rapidly changing period from mid-2002 to mid- 2003, showed that the annual decrease in breast cancer incidence was only present in women who were 50 or older. During that time period, there was an increase of 1.3% in breast cancer incidence in women under age 50 (95% CI, -3.1 to 5.8), a decrease of 11.8% for women between 50 and 69 (95% CI, 9.2 to 14.5) , and a decrease of 11.1% for women 70 and older (95% CI 7.9 to 14.2). The compelling question is, why this sharp drop, followed by a stabilization at a lower rate in women 50 and older?

As best I can tell, there are potentially, several explanations: 1. A decline in hormone use since the first report of the Women’s Health Initiative (WHI). 2. A decrease in the rate of screening mammograms. 3. A possible decrease in the rates of annual exams in women 50 and older due to discontinuing HRT 4. An error in the NCI Surveilance, Epidemiology, and End Results (SEER) data. 5. A possible general decrease in the rates of cancers in general 6. Some possible positive influence on the rates of breast cancer. A little closer examination of each of these is important.

One possible explanation that has been posed, is a reporting flaw in the SEER data. This is considered to be unlikely due to there being no significant change in the incidence of any other cancer other than breast cancer during this period. In addition, all nine SEER registries showed the same trend.

A feasible explanation might be related to a major decrease in the rate of screening mammography. For 2003, there was a decrease of 3.2% in the rate of screening mammograms between the ages of 50 and 65, compared with the year 2000. Another aspect of this influence, might be that there could be a change in the frequency and pattern of screening mammograms in women who formerly used hormone replacement therapy (HRT), and now do not. Women who receive HRT, are likely to also receive annual mammograms. Once they discontinue HRT, might they also discontinue doing annual mammograms, as well as go to the doctor less frequently for breast exams? Basically, breast cancers going undetected. Although I do think that in fact, women who discontinue HRT, do initially delay their annual screening mammograms and visits to the doctors, we have no published data showing a decrease in mammographic screening in women who discontinue HRT. In addition, women who discontinue HRT, who are 50 and older, are also disinclined to receive annual exams, especially now since they are being told they do not need an annual pap smear.

The decrease in breast cancer incidence began in mid-2002, and occurred shortly after the publication of the first report of the Women’s Health Initiative in July of 2002, which demonstrated a slight increase in the risk of breast cancer after 4 years of use. By the end of 2002, the use of conventional HRT, declined by approximately 38% in the U.S. and there were 20 million fewer prescriptions written in 2003 than in 2002. , The total number of prescriptions for Premarin and PremPro, the two most common forms of HRT, saw a steep decline starting in 2002, and especially in 2003. 62 million prescriptions were written in 2000, 61 million in 2001, 47 million in 2002, 27 million in 2003, 21 million in 2004, and 18 million in 2005. The periods of sharpest decline appeared to start in 2002 and then also in 2003.

What about some positive influence on the rates of breast cancer? Could there have been something that emerged starting in 2003? Drugs such as tamoxifen, raloxifene, nonsteroidal antiinflammatories and statins have certainly increased dramatically, and there is some evidence for the beneficial effects of these medications on the overall risk of breast cancer. However, it appears that none of these medications had a significant increased change in use during the period from 2000 to 2004. Increased utilization of vitamin D or green tea or soy products might also deserve some thought. While there is some data as to the potential positive influence of these on breast health and even reducing the risk of breast cancer, we do not have any data on increased utilization of these products distinctly in this period of 2002 to 2003.

Women who were in the Women’s Health Initiative PremPro arm when the study was discontinued, are being followed for clinical outcomes, and a report of this will likely be published later in 2007. This report will shed additional evidence related to the influence of discontinuation of HRT on the incidence of breast cancer.

Experts on the topic of HRT and breast cancer are hesitating to render any final opinion on this report while also admitting that “the ultimate understanding of the effect of cessation of hormone-replacement therapy will be complex; it will probably depend on more than one mechanism and will be affected in different ways by various forms of postmenopausal hormone-replacement therapy.”

Additional time will reveal another interesting aspect of this: will the appearance of clinically detectable tumors by mammography only be delayed, rather than an actual long term reduction in breast cancer incidence. Removing HRT may only slightly or temporarily slow the growth of tumors that already exist. If this is the case, then as the use of HRT stabilizes at a certain utilization rate, then the incidence of breast cancer would rise again.

It is my humble opinion that since the WHI and many other studies demonstrate only a slight increase in the rates of breast cancer after combined conjugated equine estrogens and progestins for 5 years or more, that any decrease in the rates of breast cancer seen in 2003, immediately post WHI, is associated with withdrawal of an agent that can slightly increase the growth of an already pre-existing tumor.

1. Ravdin P, Cronin K, Howlander N, Chlebowski R, Berry D. A sharp decrease in breast ancer incidence in the United States in 2003. Breast Cancer Res Treat 2006; 100: Suppl: S2, a abstract.
2. Ravdin P, Cronin K, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. NEJM 2007;365;16:1670-1674.
3. Rossouw J, Anderson G, Prentice R, 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; 288: 321-333.
4. Buist D, Newton K, Miglioretti D, et al. Hormone therapy prescribing patterns in the United States. Obstet Bynecol 2004; 104:1042-1050.
5. Hersh A, Stefanick M, Stafford R. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291:47-53.
6. Drug Topics. Drugs by units in the United States ion specific years. (Accessed March 29, 2007, at http://www.drugtopics.com/drugtopics/.)

This population-based cased-control study in Philadelphia consisted of 949 breast cancer cases and 1,524 controls. Herbal supplements including Black Cohosh, ginseng and red clover were the most prevalent preparations. After adjusting for potential confounding factors, Black Cohosh use was associated with a 61 percent reduction in the risk of breast cancer with an odds ratio of 0.39, 95% CI: 0.22-0.70. The breast protective effect was similar for a specific Black Cohosh preparation, Remifemin, odds ratio 0.47, 95%, CI: 0.27-0.82.

Comments: Women included in the study were those with a first primary, invasive, breast cancer of stage I, II, III, any grade and any tissue type (ductal, lobular, mucinous, papillary, mixed.) Women with ductal carcinoma in situ or lobular carcinoma in situ were excluded. This is not the first study that has indicated antiproliferative, antiestrogenic effects of Black Cohosh on breast cancer cells, especially estrogen receptor (ER) + breast cancer cells. In the current study, Black Cohosh and/or Remifemin persisted irrespective of ER status. On the other hand, the effect of Black Cohosh and/or Remifemin varied by progesterone receptor (PR) status. The effect was significant in PR positive tumors but not in PR negative tumors. This suggests that PR activity may be related to the protective effects of Black Cohosh on the breast.

While the researchers in this study, incorrectly describe Black Cohosh as containing phytoestrogens, this study is yet one more positive finding on the safety of Black Cohosh for breast cancer survivors with menopause symptoms.

The last evidence based consensus opinion of the North American Menopause Society (NAMS) was published in 2001. An expert panel of clinicians and researches in the field of calcium and women’s health followed evidence-based guidelines to make recommendations to the NAMS Board of Trustees.

Areas in the document that were addressed were calcium intake, menopausal status and calcium, target intake, calcium sources, calcium benefits, and calcium levels. Here are selected highlights from that document:

Calcium intake
Adequate calcium intake, in the presence of adequate vitamin D, has been shown to reduce bone loss in peri- and postmenopausal women as well as reducing fractures in postmenopausal women older than 60 who have low calcium intakes. Calcium also enhances the anti-resorptive effects of hormone therapy (HT) in postmenopausal women. Adequate calcium is an important aspect of any treatment regimen for women with osteoporosis.

Menopause status and calcium
Whatever age menopause occurs, the requirement for calcium increases. Calcium absorption and renal calcium conservation are both estrogen dependent and both decline in hypo-estrogen states.

Calcium amounts and sources
The target for calcium intake for most postmenopausal women is 1,200 mg/ day. Adequate vitamin D status is currently defined as a serum level of 30 ng/mL or more of 25-hydroxyvitamin D. It is recommended that foods be the primary source of calcium.

Dairy products are among the better sources of calcium due to the amount of calcium contained in a serving, ease of absorption, other nutrients in the dairy products and the affordable cost. One serving of a dairy product contains between 300 mg to 400 mg per serving, depending on the product. Calcium supplements and calcium fortified foods are available in order to reach the daily target amount. Calcium is best to take with meals and not more than 500 mg at a time to achieve maximal absorption. Calcium bioavailability varies from product to product and consumers are encouraged to confirm consistent bioavailability of a product.

Recommended daily elemental calcium intake for peri-and postmenopausal women:

Institute of Medicine

Aged 31-50 [1,000 mg]
Aged 51 and older [1,200 mg]

National Institutes of Health

Premenopausal women aged 25-50 [1,000 mg]
Postmenopausal women younger than age 65 and using estrogen therapy 1,000 mg
Postmenopausal women not using estrogen therapy [1,500 mg]
All women aged 65 and older [1,500 mg]

Osteoporosis Society of Canada

Menopausal women [1,500 mg]

Calcium benefits
Calcium is beneficial in protection of bone mass and slowing of bone loss, small risk reduction of colorectal cancer, hypertension, renal calculi, PMS and obesity.

Calcium levels
No accurately sensitive tests are available to assess calcium deficiency. The focus should be on the recommended guidelines and to encourage women to consume adequate calcium and/or take calcium supplements. The laboratory test for serum vitamin D is available to diagnose those women who are vitamin D deficient and thus more likely to be deficient in calcium.

The average daily dietary consumption of calcium is far below the recommended amount to achieve optimal bone health. Health care providers are encouraged to be more vigilant in advising peri- and postmenopausal women regarding calcium intake.

Derived from the tea plant Camellia sinensis, green tea is very high in polyphenols which have potent antioxidant and anti-tumor properties. The major polyphenols in green tea are flavonoids, including catechin, epicatechin, epicatechin gallate, epigallocatechin gallate, and proanthocyanidins. Epigallocatechin gallate (EGCG) is thought to be the most significant active component of green tea. Products with higher EGCG content, are thought to be more potent. Other compounds in green tea include vitamin C, a very small amount of caffeine, theanine, lignins, organic acids, protein and chlorophyll.

The catechins in green tea are thought to have anti-inflammatory activity by COX-1 and COX-2 inhibition, leukotriene inhibition, and nitric oxide synthetase activity. Green tea flavonoids might also reduce lipoprotein oxidation, reduce proliferation of vascular smooth muscle and inhibit the release of arachidonic acid from platelets. However, when used in humans, green tea has not yet shown any consistent effect on cardiovascular risk factors.

A study was recently published in JAMA to investigate the associations between green tea consumption and all-cause and cause-specific mortality. It is called the Ohsaki study, a population-based, prospective cohort study. This study. included Japanese adults aged 40-79 without a history of stroke, coronary heart disease or cancer, at initiation of the study. They were followed for up to 11 years for all cause mortality and for up to 7 years for cause-specific mortality. Green tea consumption was inversely associated with mortality due to all causes and inversely associated with cardiovascular disease. This inverse association for all-cause mortality association and for cardiovascular disease was stronger in women and even a greater association with cardiovascular disease.

Unfortunately, there was no beneficial effect of green tea consumption and reducing the hazard ratio of cancer mortality.

Despite lack of clarity regarding green tea and cancer prevention in humans, there are mechanisms of action of green tea that are compelling: Green tea may protect against some kinds of cancers by preventing blood vessel growth in tumors, inducing apoptosis, reducing oxidative DNA damage, inhibiting tumor promoters, inhibiting hormones and growth factors with the receptor sites, reducing free radical generation and inhibiting important enzyme systems necessary for cancer promotion and proliferation.

Green tea and cancers

Laboratory studies demonstrate that the catechins in green tea, particularly EGCG, inhibit tumor formation and growth through several mechanisms. EGCG has been shown to induce apoptosis in cancer cells lines from prostate, stomach and epidermoid cancers.

Green tea polyphenols have induced apoptosis and inhibited lung cancer cell proliferation in vitro as well. Other examples of in vitro inhibition of EGCG on cancer cells have included colorectal and breast cancer cells.

Breast Cancer

There have been numerous in vitro and animal studies showing the effects of green tea on reducing as well as preventing breast tumors and inhibiting various enzymes and cell signaling systems. EGCG has demonstrated the ability to inhibit the growth of human breast and prostate tumors transplanted into athymic mice. Green tea extracts given to female rats significantly decreased DMBA-induced mammary tumor burden, invasive tumors, and significantly delayed the onset of a first tumor. Another study fed Sprague-Dawley rats 1% green tea catechins in the diet, was effective in reducing breast tumor promotion, but not the progression of breast cancer. Several in vitro studies have found green tea reduced the rate of proliferation of breast cancer cells.

More recently, green tea extract and EGCG affected angiogenic factor vascular endothelial growth factor (VEGF) expression. The extract or the EGCG significantly decreased the levels of the VEGF peptide secreted into the medium of human breast cancer cells. The green tea was also able to suppress the expression of protein kinase C, a VEGF transcription modulator, and decrease the RNA levels of VEGF. Inhibition of VEGF transcription appears to be involved in the antiangiogenic effects of green tea.

The implication being that green tea could inhibit blood supply to breast cancer tumors or breast cancer cell target sites by inhibiting VEGF and may have potential use for breast cancer treatment and prevention.

Breast tumors which are HER-2 neu positive may also be especially susceptible to green tea. EGCG inhibited mouse mammary tumor HER-2 neu cell growth in vitro, and dose of green tea polyphenols slowed the growth of estrogen receptor-negative breast cancer cell lines.12

In 1998, a study found the more green tea pre-menopausal women with stage I and stage II breast cancer consumed, the fewer metastasized lymph nodes they developed. Additionally, postmenopausal women who consumed green tea experienced an increased progesterone and estrogen status – a finding usually associated with less aggressive forms of breast cancer. No benefit was seen in stage III breast cancer patients. In stage I and II patients, there was a 16.7% recurrence rate for those consuming five cups or more of green tea (with an average of eight cups) per day. For those who consumed four or fewer cups per day (with an average of two), there was a 24.3% recurrence rate. Disease-free survival was also significantly improved in stage I and stage II breast cancer patients who had a greater consumption of green tea, compared to those who consumed less green tea.

Epidemiologic studies, both case-control and cohort in design, have examined the association between tea intake and breast cancer. A meta-analysis of 13 papers provided data on green tea and black tea. For black tea, there were conflicting results in case-control versus cohort studies. Of the eight case-control studies, there was a minor inverse association between black tea and risk of breast cancer. Five cohort studies demonstrated a modest increase in risk associated with black tea intake. However, the results for green tea indicated a lower risk for breast cancer with green tea consumption.

Ovarian Cancer

New research has raised the possibility that green and black tea may reduce the risk of ovarian cancer. Investigators evaluated the association between tea consumption (mainly black tea) and the risk of ovarian cancer in women aged 40-76. During an average of 15 years and in 61,057 women, tea consumption was inversely associated with ovarian cancer risk. Compared with women who rarely or never consumed tea, those who drank 2 or more cups daily had a hazard ratio of 0.54 (95% CI, 0.31-0.91) for ovarian cancer. Risk reduction was independent of age of menarche, age at first birth, age at menopause, family history of breast cancer and use of hormone replacement therapy.

Tea consumption may also enhance the survival of women with epithelial ovarian cancer. A cohort of 254 women with confirmed ovarian cancer was followed for a minimum of 3 years. The survival was greater with tea drinkers who consumed at least 1 cup of green tea per day compared to non tea drinkers.

Cervical Dysplasia and HPV

Green tea has recently been shown to influence numerous mechanisms which are favorable towards preventing and/or treating HPV related lesions. Epigallocatechin-3-gallate has been shown to inhibit epidermal growth factor receptor (EGFR) signaling pathway. EGFR activation is required for cervical cell proliferation which suggests agents which inhibit EGFR may be of important therapeutic value in prevention and treatment of cervical dysplasia and genital warts. Two other in vitro studies demonstrated EGCG inhibits the growth of human cervical cancer cell lines, induces apoptosis, inhibits telomerase activity in cervical cell lines and has a role in regulation of gene expression.

Perhaps the most encouraging of the studies was an investigation of the clinical efficacy of green tea extracts delivered vaginally and/or orally in patients with HPV infected cervical lesions. Fifty-one patients with cervical lesions ranging from chronic cervicitis, mild dysplasia, moderate dysplasia and severe dysplasia were divided into four groups as compared with 39 controls. A green tea polyphenol vaginal product was applied locally twice a week to 27 patients. 20 of the 27 patients using the vaginal green tea product showed a response. An oral 200 mg EGCG capsule was taken orally every day for eight to 12 weeks in six patients and three out of the six showed a response. Group three consisted of eight patients using the vaginal product and the oral capsule. Six of eight showed a response. Group 4 consisted of 10 patients using a higher dose EGCG capsule (amount not stated). Six out of the 10 patients with this higher dose EGCG oral capsule only, showed a response. Overall, 35 of 51 (69%) response rate was noted for the green tea products compared with a 10% response rate in the untreated controls. The mechanisms involved appear to be apoptosis, cell cycle arrest, modification of gene expression and anti-tumor effects, specifically, inhibition of cell proliferation. These results demonstrate green tea extracts in the form of a vaginal delivery and an oral capsule are effective strategies for treating cervical lesions.

Weight loss

Green tea may also play a role in weight management. An increase in fat and calorie metabolism may be caused by the caffeine, catechin and theanine constituents. They appear to stimulate thermogenesis as a means of increasing fat burning and inhibiting fat absorption. In addition, individuals who take green tea extract have been observed to expend more energy and burn more calories than those who do not. In this study demonstrating the thermogenic properties and fat oxidation of green tea, done in Geneva in 1999, the higher dose used contained 50 mg of caffeine and 90 mg of EGCG per 2 capsules. According to this study, dosing is 2 caps with breakfast and 2 caps with lunch.

Polycystic ovarian syndrome

Green tea’s ability to increase the production of sex-hormone-binding globulin and its thermogenic effect also provides a rationale for its use in women with polycystic ovarian syndrome (PCOS). By increasing sex hormone-binding globulin, some free testosterone can be bound up, thereby reducing some of the testosterone-related problems seen in women with PCOS such as hair thinning, acne and facial hair. Obesity is another consideration in approximately 50% of PCOS women. Green tea may be helpful in not only increasing SHBG, but also in the thermogenic effects and weight loss potential.

Cognitive Impairment

Dementia, especially Alzheimer’s Disease, is more common in women than in men. Considerable in vitro and animal evidence shows green tea may possess neuroprotection, help to reduce amyloid precursor protein and scavenge free radicals. These effects may offer enhancement of cognitive function, but no human data has existed until very recently. Higher consumption of green tea, in men and women, was associated with a lower prevalence of cognitive impairment. This study showed an inverse dose response relationship between consumption of green tea and the prevalence of cognitive impairment.

Side effects and dosing

Some individuals are negatively affected by the small amount of caffeine in
green tea and its stimulating effect, leading to nervousness, insomnia, dizziness, agitation, restlessness, confusion and anxiety. These effects are more common when using higher doses of green tea. Some individuals may also have an increase in blood pressure or pulse, especially if consumed in higher amounts and in those who already have even mild hypertension. Allergic reactions can occur and tend to include cough, dyspnea, loss of consciousness and asthma. Rare anaphylaxis reactions can occur to the caffeine in green tea.

Another consideration is withdrawal from the green tea. Although uncommon, withdrawal symptoms have been known to occur, including anxiety, restlessness, muscle tension, nausea and vomiting.

Combining ephedra with caffeine can increase the risk of adverse events including hypertension, seizures, and temporary loss of consciousness. Avoid use during pregnancy and while nursing. Infants whose nursing mothers consume caffeine could suffer from sleep disorders.

The Natural Medicines Comprehensive Database lists the following drugs as have potential adverse interactions with green tea: Adenosine, Alcohol, amphetamines, cimetidine, clozapine, cocaine, contraceptives, disulfiram, ephedrine, estrogens, fluconazole, lithium, monamine oxidase inhibitors, nicotine, quinolone antibiotics, theophylline, verapamil and clopidogrel, ticlopidine, heparin and warfrain.

When dosing green tea capsules, those containing 300 mg of green tea extract with 95% polyphenols, 80% catechins and 55% EGCG, 1 capsule is approximately equal to 3 cups of green tea. The normal amount of green tea consumed traditionally by Japanese adults is about three cups per day, providing about 240 to 320 mg of polyphenols. Green tea suppositories are also now available for use in HPV and cervical dysplasia management.

Summary of Clinical concepts

1. Breast Cancer stage I or II= 2-3 green tea extract capsules (containing 95% polyphenols, 80% catechines and 55% EGCG per day) per day or 5-8 cups of tea daily.
2. Ovarian cancer prevention= 1 cup per day
3. Ovarian cancer treatment adjunct= 2 cups per day
4. Cervical atypia= green tea suppositories twice weekly plus one green tea extract capsule per day
5. Cervical dysplasias= as part of a comprehensive systemic and local treatment strategy, also include one green tea capsule daily and green tea suppositories twice weekly
6. Weight loss= 2 caps of green tea extract with breakfast and 2 with lunch (2 caps = 50 mg caffeine and 90 mg of EGCG)
7. PCOS= 250-500 mg of green tea extract per day (95% polyphenols, 80% catechins, 45% EGCG)

Citations

1. Kuriyama S, Shimazu T, Ohmori K, et al. Green tea consumption, and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA 2006 Sept 13; 296 (10): 1255-1265.
2. Paschka A, et al. Induction of apoptosis in prostate cancer cell lines by the green tea components, epigallocatechine-3-gallate. Cancer Lett 1998;130(1-2):1-7
3. Hibasami H, et al. Induction of apoptosis in human stomach cancer cells by green tea catechins. Oncol Rep 1998;5:527-529.
4. Ahmad N, et al. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881-1886.
5. Yang G, et al. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis 1998;19:611-616.
6. Chen Z, et al. Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts. Cancer Lett 1998;129:173-179.
7. Liao S, Umekita Y, Guo J, et al. A growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Letters, 1995; 96:297-301.
8. Kavanagh, K, Hafer L, Kim D, et al. Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture. J Cell Biochem 2001; 82: 387-398.
9. Hirose M, Hoshiya T, Akegi K, et al. Inhibition of mammary gland carcinogenesis by green tea catechins and other naturally occurring antioxidants in female Sprague-Dawley rats pretreated with 7,12-dimethylbenz(a)anthraacene. Cancer Lett 1994;83:149-156.
10. Kavanagh, K, Hafer L, Kim D, et al. Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture. J Cell Biochem, 2001; 82:387-398.
11. Araki R, Inoue S, Osborne M, Telang, N. Chemoprevention of mammary preneoplasia. In vitro effects of a green tea polyphenol. Ann N.Y. Acad Sci, 1995;768;215-222.
12. Sartippour M, Zhi-Ming S, Heber D, et al. Green tea inhibits vascular endothelial growth factor induction inhuman breast cancer cells. N Nutr 2002;132:2307-2311.
13. Pianetti S, Guo S, Kavanagh K, Sonenshein G. Green tea polyphenol epigallocatechin-3 gallate inhibits Her-2/Neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res 2002;62:652-655
14. Nakachi K, Suemasu K, Suga K, et al. Influence of drinking green tea on breast cancer malignancy among Japanese patients. Japan J Cancer Res 1998;89:254-261
15. Sun C, Yuan J, Koh W, Yu M. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis 2006;27(7): 1310-1215.
16. Larsson S, Wolk A. Tea consumption and ovarian cancer risk in a population-based cohort. Arch Intern Med 2005;165(22): 2683-2686
17. Zhang M, Lee A, Binns C, Xie X. Green tea consumption enhances survival of epithelial ovarian cancer. Int J Cancer 2004;112(3): 465-469.
18. Sah J, Balasubramanian S, Eckert R, Rorke E. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibit of ERK _ and AKT kinases. J Biol Chem 2004;79(13): 12755-12762.
19. Ahn W, Huh S, Bae S, et al. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis G(1) arrest, and regulation of gene expression. DNA Cell Biol 2003;22(3): 217-224.
20. Yokoyama M, Noguchi M, Nakao Y, et al. The tea polyphenol, (-) – epigallocatechin gallate effects on growth, apoptosis, and telomerase activity in cervical cell lines. Gynecol Oncol 2004;92(1): 197-204.
21. Ahn W, Yoo J, Huh S, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Preve 2003;12(5): 383-390.
22. Dulloo, A, et al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-hour energy expenditure and fat oxidation in humans. Am J Clin Nutr 1990;70:1040-1045
23. Nigata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenstrual Japanese women. Nutrition and Cancer 1998;30(1): 21-24.
24. Kuriyama S, Hozawa A, Ohmori K, et al. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project. Am J Clin Nutr 2006;83:355-361.

Some initial thoughts…

Women’s health problems include health issues that occur only in women, (PMS, vaginitis, fibrocystic breasts, etc), issues that occur more commonly in women (osteoporosis, breast cancer, bladder infections, depression, etc), and medical problems that have unique characteristics when found in women (heart disease, cognitive function, herpes, etc). Many of these problems are more frequent nowadays than they were in previous years- conditions like PMS, fibrocystic breasts, depression, and genital herpes are increasing in their incidence and sometimes severity. Although the reasons may not always be clear, these changes can at least in part be explained by a decline in nutritional habits and exercise. Other factors include a decline in the quality of our environmental, social and financial pressures, and changes in social relationships. Women are also living longer, as many as 40 more years now than several decades ago. For women, this means we are living about 30 or more years past menopause. This leaves us at an increased risk for osteoporosis, heart disease and breast cancer to name a few. These life threatening problems for women need special attention- in both prevention and treatment.

Whether it is prevention or treatment, it is important to understand the basics: exercise, nutrition, fresh air, rest, and attention to our emotional and spiritual life. Herbal and nutritional supplements are best used in a context of these basics. A life of healthy living reaps its best rewards when started young. Augmenting these fundamental health practices with selected herbal and nutritional supplements specific to your medical history, hereditary issues and current health problems, provide a very comprehensive holistic approach to disease prevention and intervention.

I hope you find these writings and suggestions helpful to you. I wish you good health for the coming year.