Dr. Tori Hudson, N.D.

Folic acid update

It has been known for a considerable amount of time, that folic acid when given to women planning for pregnancy and during pregnancy, can lower the risk for neural tube defects. Based on the research up to that time, the US Preventive Services Task Force (USPSTF) first published their recommendations in 1996. This has recently been updated and the USPSTF has issued a new statement in May, 2009. Based on the observational evidence and randomized controlled trials published since 1996, the USPSTF found convincing evidence that supplements containing 0.4 to 0.8 mg of folic acid during the preconception period lowers the risk for neural tube defects.[1]

 

There now appears to be additional benefits for folic acid before conception and during pregnancy, possibly the prevention of cleft lip (BMJ 2007;334:464) and most recently, lowering the rates of severe congenital heart defects. In a Quebec study, investigators observed a drop in the prevalence of severe congenital heart defects after mandatory folic acid fortification of grains. The average prevalence of severe congenital heart defects at birth was 1.64 per 1000 births during the 9 years before the folic acid food fortification began and the rate fell by 6.2% yearly during the seven years studied, after the mandatory fortification.[2]

Following the recommendation that all women of child bearing age should take a daily supplement containing 0.4 mg to 0.8 mg per day of folic acid is good, safe medicine and perhaps even more beneficial than previously thought.

References

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[1] Woffe T, Takacs-Witkop C, Miller T, Syed S. Folic acid supplementation for the prevention of neural tube defects: An update of the evidence for the U.S. Preventive Services Task Force. May 2009.150; (9): 632-639

[2] Ionescu-Ittu R, et al. Prevalence of severe congenital heart disease after folic acid fortification of grain products: Time trend analysis in Quebec, Canada. BMJ 2009;338:b1673

St. John’s Wort and menopause symptoms

St John’s wort was compared with a placebo in a double-blind, randomized clinical trial on symptoms and quality of life issues in perimenopausal women. Forty-seven 40 to 65 y.o. perimenopausal women who experienced three or more hot flashes per day were randomized to receive either 900 mg three times daily of a St. John’s wort extract or placebo for 3-months. Hot flash severity and frequency were evaluated and the Menopause-Specific Quality of Life questionnaire was used to evaluate menopause related quality of life.

After 12 weeks, only a small difference was seen favoring St. John’s wort in the frequency of hot flashes. A 30% improvement in 50% of the women was seen in the St. John’s wort group and only 23% in the placebo group. A significant reduction in sleep problems and depression was seen with St. John’s wort and the St. John’s wort group scored significantly better with menopause related quality of life.

References

Al-Akoum M, Maunsell E, Verreault R, et al. Effects of Hypericum perforatum (St. John’s wort) on hot flashes and quality of life in perimenopausal women: a randomized pilot trial. Menopause 2009; 16(2):307-314

Folic acid updates for pregnant women

The US Preventive Services Task Force (USPSTF) has issued a new updated statement in the May 5 issue of Annals of Internal Medicine. This statement is an update of the 1996 USPSTF recommendation that all women planning or capable of pregnancy take a multivitamin supplement containing folic acid to prevent neural tube defects. Based on the observational evidence and randomized controlled trials published since 1996, the USPSTF found convincing evidence that supplements containing 0.4 to 0.8 mg of folic acid during the preconception period lowers the risk for neural tube defects. They also concluded that adequate evidence suggests that folic acid from supplementation at usual doses is not associated with serious harms including no evidence found for the masking of vitamin B₁₂ deficiency in women of childbearing age. For women who are planning or are capable of pregnancy, the USPSTF concludes that there is a high certainty that the overall benefit of folic acid supplementation during pregnancy is substantial.

References

Woffe T, Takacs-Witkop C, Miller T, Syed S. Folic acid supplementation for the prevention of neural tube defects: An update of the evidence for the U.S. Preventive Services Task Force. May 2009.150; (9): 632-639

One of the most eye opening experiences I’ve had in relationship to cardiovascular disease was hearing a lecture and reading an article by John Abramson, M.D. In an interview with Dr. Abramson published in TLFD June 2008, he states that “there is not a single randomized controlled trial that shows that cholesterol-lowering statin drugs are beneficial for women of any age or men over 65 who do not already have heart disease or diabetes.” He also sates that even the 2001 National Cholesterol Education Program guidelines admit that clinical evidence for their recommendations regarding statins for women was generally lacking and it was based on extrapolation of the data from men. He also asserts that there’s no evidence for men or women over age 65, who do not have heart disease or diabetes, that statins reduce cardiovascular events.

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

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[1] Tuttle K, Shuler L, Packard D, et al. Comparison of low-fat versus Mediterranean-style dietary intervention after first myocardial infarction (from the Heart Institute of Spokane Diet Intevention and Evaluation Trial). Am J Cardiol 2008;101:1523-1530.

[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.

Sixteen healthy women who had taken a low dose oral contraceptive (OC) with 20 mcg ethinylestradiol + 0.15 mg desogesterol for at least 3 months participated in this study. A 50% ethanol extract of St. John’s wort 250 mg twice daily standardized to 0.2% hypericin (1 mg/day) and < 0.2%(< 1mg/day) hyperforin was initiated day 7 through day 21 of the of the OC administration. Blood samples were taken on day 7 and 14. The activities of CYP3A4 for the estrogen metabolism, and CYP2C19 and CYP2D6 for the progestin metabolism were used to measure metabolism of the OC and interaction of the OC with St. John’s wort. Results demonstrated that co-medication of the St. John’s wort extract with the oral contraceptive did not elicit any differences in the pharmacokinetic measures of ethinylestradiol in this study.

The pharmacokinetics of the desogestrol was also not affected by co-administration of the St. John’s wort extract. There was a small decrease in ethinylestradiol and 3- ketodesogestrel but it was not considered significant. In addition, there was no break through bleeding induced by the addition of the St. John’s wort extract.[1]

Comments

The results of this study are in contrast to other previous reports and studies. Two reports have shown break-through bleeding and spotting with co-administration of St. John’s wort and OCs.[2],[3]

Three studies indicate an alteration of the pharmacokinetics of the OC with co-administration of St. John’s wort. [4], [5], [6] These studies used a different St. John’s wort preparation (80% methanolic extract) and at a much higher dose (900 mg) containing a much higher amount of hyperforin (20-35 mg) than the current study.

The lower daily total dose and hyperforin intake would appear to be the likely reason for the lack of interaction of the St. John’s wort extract with the OC pharmacokinetics in this current study. Accordingly, using a lower dose St. John’s wort extract with reduced hyperforin content does not appear to interact with OC nor cause breakthrough bleeding (an indication of possible ovulation).

References

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[1] Will-Shahab L, Bauer S, Kunter U. St John’s wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive. Eur J Clin Pharmacol 2009; 65:287-294.

[2] Ernst E. Second thoughts about safety of St. John’s wort. Lancet 1999;354:2014-2016.

[3] Raetz A, vonMoos M, Drewe J. Johanniskraut: ein Phytopharmakon mit potentiell gefahrlichen Interaktionen. Praxis 2001;90:843-849.

[4] Pfrunder A, Schiesser M, Gerber S, et al. Interaction of St. John’s wort with low-dose oral contraceptive therapy: a randomized controlled trial. Br J Clin Pharmacol 2003;56:683-690

[5] Hall S, Wang Z, Huang S, Hamman M, et al. The interaction between St. John’s wort and an oral contraceptive. Clin Pharmacol Ther 2003; 74:525-535.

[6] Murphy P, Kern S, Stanczyk F, Westhoff C. Interaction of St. John’s wort with oral contraceptives: effects on the pharmacokinetics of norehindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception 2005;71:402-408

One hundred and fifty reproductive aged women with primary dysmenorrheal (menstrual cramps) were divided into three groups, in a double-blind clinical trial. Group one received ginger rhizome powder capsules, 250 mg four times a day for three days starting day one of their menses. The second group received 250 mg mefenamic acid capsules, four times daily days one through three, and the third group took 400 mg ibuprofen capsules four times daily again, days one through three of the menses. Assessment was performed after one menstrual period.

At the end of treatment, the severity of dysmenorrhea decreased in all groups and no differences were found between the groups in pain severity, pain relief or satisfaction. More women in the ginger group became completely pain free, vs. the mefenamic acid and ibuprofen groups. The rate of satisfaction from the treatments was 20/50 women in the mefenamic acid group, 22/50 women in the ibuprofen group and 21/50 women in the ginger group.

The cause of menstrual cramps is thought to be due to an increased production of prostaglandins in the endometrium (lining of the uterus). Menstrual blood of women with primary dysmenorrhea has greater amounts of the prospasmodic and proinflammatory prostaglandins, PGE2 and PGF2 alpha. Both mefenamic acid and ibuprofen act as inhibitors of the synthesis of these prostaglandins. It is thought that the anti-inflammatory properties of ginger are due to the gingerols, also leading to and prostaglandin reduction as well as some inflammatory substances. Consider using ginger root either alone, or in combination with other important natural ingredients in the relief of menstrual cramps such as cramp bark, niacin, vitamin B6, valerian, wild yam and more.

References

Ozgoli G, Goli M, Moattar F.  Comparison of effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea.  J Alternative and Complementary Med 2009; 15(2):129-132.

1739 offspring (Caucasian) of the original Framingham Heart Study were eligible for the Framingham Offspring Cohort.  Mean age was 59 years, 55% were women (947) were without prior cardiovascular disease.  25-hydroxyvitamin D levels were measured and deficiency groups were identified as < 15 ng/mL and < 10 ng/mL. 28% of individuals had levels < 15 ng/mL and 9% had levels < 10 ng/mL. With an average follow-up of 5.4 years, 120 participants developed a first cardiovascular event. Those with a serum vitamin D level < 15 ng/mL had a hazard ratio of 1.62 for cardiovascular events compared with those with a 25(OH)D level > 15 ng/mL. This effect was observed in those with hypertension but not those without.  There was a progressive increase in cardiovascular risk with lower levels of vitamin D with a 1.53 hazard ratio for levels 10 to < 15 ng/mL and 1.80 for levels < 10 ng/mL. 
Commentary

The results of this study suggest that a moderate to severe vitamin D deficiency is a risk factor for developing cardiovascular disease.  One would hope that treatment of vitamin D deficiency with vitamin D supplementation or adequate exposure to sunlight could reduce that risk.  While a randomized intervention trial would be needed to assess vitamin D supplementation as a treatment strategy, we do have other positive evidence showing vitamin D supplementation reducing blood pressure, ventricular hypertrophy and inflammatory cytokines.
References

Want T, Pencina M, Booth S, et al.  Vitamin D deficiency and risk of cardiovascular disease.  Circulation. 2008; 117: 503-511.

The potential for soy protein or soy isoflavones to alter bone metabolism and bone resorption is currently contradictory and inconclusive.  The lack of agreement in the literature is thought to be related to variations in study design. These variations in study design include differences in the dosage and form of soy products studied, (i.e. soy protein isolate, whole soy foods, or extracted soy isoflavones), differences in the menopausal status of the women studied, (i.e. perimenopausal, early menopausal or late postmenopausal) differences in the duration of the various trials, and differences in the tests used to assess bone density and bone metabolism.  All of these different approaches and study designs make it very difficult to determine the effectiveness of soy for bone health, and make the decision to include soy in a protocol for supporting bone health more difficult for the practitioner.

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 non-traumatic events.  Bone turnover is an independent predictor of fracture risk.  While research on 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 increasing bone density in women.  Soy appears to have an estrogenic effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in a study in which soy replaced casein in the diet and 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 osteoclasts, the cells responsible for bone resorption, both in the test tube and in vivo.  Arjmandi also did a double-blind, randomized, and 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 soy 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 isoflavone diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip. Soy isoflavones seem 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 of ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging. 

An analysis of the relationship of soy isoflavone intake and bone mineral density was conducted from 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, median intakes of genistein were too low to pursue analyses. For Chinese women, no association between genistein and bone mineral density was found. Premenopausal, but not perimenopausal Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. The 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 recent meta-analysis further increases our optimism about using soy to inhibit bone resorption.  Nine studies with a total of 432 menopausal women were evaluated in this 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), a marker of bone turnover, demonstrated that those who consumed isoflavones had a decrease in these biomarkers of -2.08nmol/mmol, when compared to those who did not consume isoflavones.  In five of the studies where isolated soy protein was used there was no significant effect on urinary deoxypyridinoline.  In the current analysis, a significant reduction in urinary deoxypyridinoline was not observed in those studies with isoflavones of less than 90 mg/day.  In a review of the research in 2003, the author concluded that 90 mg 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 meta-analysis mentioned above which analyzed nine studies the significant effects on urinary peptides occurred in Asian women but not Caucasian women.  This may be due to the conversion of daidzein into its active metabolite equol by intestinal flora, and by the fact 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.

A nutritional influence of soy foods that may be overlooked is the amount of calcium in some of these foods or in diets that contain 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.
 

CALCIUM CONTENT OF SELECTED SOY FOODS

Soy Product	Serving Size	Mg of Calcium
Tofu, firm	¼ block	553 mg
Tofu, regular	¼ block	406
Soy milk, Calcium fortified	1 cup	80-300
Soy milk	1 cup	7
Soybeans, Roasted	¼ cup	119
Soybeans, Boiled	¼ cup	88 mg
Tempeh	¼ cup	77

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.  For these women who already have osteoporosis, I am in favor of proven conventional therapies to reduce fracture risk 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), and dietary and exercise advice.

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 DF, Qin LQ, 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 isoflavones 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.

  Mei J, 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.

A small randomized, double-blind, placebo-controlled, crossover trial of fourteen postmenopausal women was completed using 3.5 gm of powdered Maca (Lepidium meyenii) for 6 weeks and matching placebo for 6 weeks. Measurements of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone binding globulin (SHBG) were taken at baseline, and weeks 6 and 12. The Greene Climacteric Scale was used to assess the severity of menopause symptoms. Serum concentrations of estradiol, FSH, LH and SHBG were similar in both groups. The Greene Climacteric Scale revealed a significant reduction in psychological symptoms including anxiety, depression and sexual dysfunction after Maca consumption compared with baseline and -placebo. These findings were independent of androgenic or alpha-estrogenic activity present in the Maca using assays to measure hormone-dependent activity.

Commentary

This study on a Maca preparation adds to the growing body of evidence utilizing Maca for menopause related symptoms. Having significant effects on anxiety and depression is terrific, but many women - in this study appear to be independent of any measurable influence on sex hormones or SHBG and presumably therefore independent of any action related to the activity of beta-sitosterol, found in Maca. These findings are not consistent with Meissner et al. (Meissner H et al. Use of gelatinized Maca [Lepidium peruvianum] in early postmenopausal women- a pilot study. Int J Biomed Sci 2005;1:33-45) who reported an elevation in LH and estradiol and a decrease in FSH. These variable results may be due to differences in dosing, type of commercial preparation used in each study, species or variety of Lepidium from which the preparations are made, extraction protocols and delivery techniques. The effect on depression and anxiety are consistent in several studies and it is thought that the flavonoids in Maca inhibit monoamine oxidase activity. The improvement in sexual function in postmenopausal women observed in this study is consistent with research using Maca in men and also in rodents.

References

• Brooks N, Wilcox G, Walker K, et al. Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content. Menopause 2008;15(6):1157-1162.

Fifty-three postmenopausal women completed a trial whereby they were randomly assigned to one of two groups: two capsules of Trifolium pratense (80 mg red clover isoflavones) daily for 90 days, or placebo.  Subjects were crossed-over for another 90 days after a 7 day washout period.  Total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C) and lipoprotein A (LpA) levels were assessed at baseline, 90 and 180 days.  Women were also subdivided into those with BMI > 25 kg/m2  and those with BMI ≤ than 25 kg/m2.

Isoflavones derived from Trifolium pratense had a beneficial effect on the lipid profile of postmenopausal women with a BMI > 25. There was also a significant decrease in TC ( 4.6%) LDL-C (15.6%) and LpA levels  (63.8%) in those that received the red clover isoflavones.

Commentary

At least five previously published reports of T. pratense isoflavones on lipid profiles in men and premenopausal and postmenopausal women have been positive, and at least two have shown no effect. This is the first published report on postmenopausal women with an increased BMI using T. pratense isoflavones to lower lipids. These decreases in TC, LDL-C and LpA correlate with findings that support a meaningful reduction in cardiovascular risk, and even more so in postmenopausal women with high lipid values. This study is promising and provides another important lifestyle supplemental tool for women who do not want to use or may not be good candidates for hormonal or statin therapies to lower their risk of cardiovascular disease.

References

• Chedraui P, San Miguel G, Hidalgo L, et al. Effect of Trifolium pratense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index. Gynecological Endocrinology 2008;24(11):620-624.

36,282 postmenopausal women were enrolled in a Women’s Health Initiative clinical trial to determine the effects of calcium and vitamin D on the incidence of hip fracture. Invasive breast cancer was a secondary outcome measure. Patients were randomly assigned to 1000 mg of calcium with 400 IU of vitamin D3 daily, or placebo for an average of 7.0 years. Mammograms, breast exams, serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 breast cancer cases and 1067 controls. The risk of breast cancer associated with random assignment to calcium with vitamin D3 was estimated using a mathematical model. The incidence of invasive breast cancer was similar in the calcium with vitamin D group compared to the placebo group, and baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk after adjusting for body mass index and physical activity. These results do not support a relationship between total vitamin D supplemental intake and 25-hydroxyvitamin D levels with breast cancer risk.

Commentary

This randomized, double-blind, placebo-controlled trial of daily supplementation of 1000 mg of elemental calcium with 400 IU vitamin D3 had no effect on the incidence of breast cancer. Some observational studies have demonstrated an association between higher calcium and vitamin D intake and reductions in breast cancer risk in postmenopausal women, while others have not. Studies in postmenopausal women have also been mixed in showing an association with lowered breast cancer risk in those with higher serum levels of 25-hydroxyvitamin D. Several thoughts regarding these mixed results are worth considering: 1) Different thresholds of serum 25-hydroxyvitamin D are used to assess associations and it may be that a higher threshold (52 nmol/L says some research; 75 nmol/L says other research) is needed to show an association. 2) Higher doses of vitamin D may be needed to demonstrate consistent results. 3) The doses of vitamin D used in different trials are not consistent. 4) The seven year duration of the current study may be insufficient given the latency of breast cancer. 5) Results may be confounded by lean women vs. overweight or obese women, recreational activity and sunlight exposure.

Given the wide variety of preventive effects of vitamin D supplementation, the multiple disease reduction benefits associated with higher serum levels, and the selected benefits on intervention with supplementation, for now, I will continue to be assertive in vitamin D dosing. The list of benefits and potential benefits spans so many diseases (heart disease, hypertension, peripheral vascular disease, osteoarthritis, osteoporosis, fractures, autoimmune diseases, depression, insulin resistance, ovarian cancer, breast cancer, colon cancer), that it remains compelling to recommend one of the most economical and safe supplements currently available.

References

• Chlebowski R, Johnson K, Kooperberg C, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 2008 100: 1561.