In the newest of the St. John’s wort studies in perimenopausal/menopausal women, a total of 100 Iranian women with an average age of 50 participated in a randomized, double-blind, placebo-controlled clinical trial comparing St. John’s wort with placebo in the treatment of hot flashes.[1] 50 women received 20 drops three times daily of St. John’s wort extract (Hypericin) that contained hypericin 0.2 mg/mL and 50 women received a placebo of distilled water. The study duration was two months. Clinical exams and interviews were performed at baseline, 4 weeks and 8 weeks. Treatment effectiveness was measured evaluating frequency, duration and severity of hot flashes as the main objective of the study.

In women taking St. John’s wort, the frequency began to decline during the 1^st and 2^nd months, but showed more improvement during the 2^nd month. There was no statistical change in hot flash frequency during the first month of placebo but did improve during the second month. Women who used St. John’s wort showed more improvement in hot flash frequency than placebo. The decline in duration of hot flashes was statistically significant at week 8 and the decline was much more evident in the St. John’s wort group. The severity of hot flashes was relieved in the St. John’s wort group during the 2 months of treatment and was more significant in the second month. Women in the placebo group did not show any significant decrease in severity of hot flashes during the 1^st month, but they did have some improvement during the 2^nd month, but not as great as those women in the St. John’s wort group.

Comments

St. John’s wort has emerged as an important clinical tool in treating perimenopausal/menopausal women—for hot flashes and/or depression and/or mood swings, and/or sleep problems either as an encapsulated standardized extract from 300 mg twice per day to three times per day, or a tincture/liquid extract ½ tsp 2-3 times per day, or in combination with other menopause therapies such as black cohosh, maca extract, kava or others.

Reference

[1] Abdali K, Khajehei M, Tabatabaee R. Effect of St. John’s wort on severity, frequency, and duration of hot flashes in premenopausal, perimenopausal and postmenopausal women: a randomized, double-blind, placebo-controlled study. Menopause 2010;17(2): 326-331.

Results: The botanical combination reduced the number of vasomotor symptoms by 46% from baseline compared with 26% in the placebo group. Forty-three percent of women taking the botanical had at least a 50% reduction in the number of symptoms compared with only 6% in the placebo group.

Commentary: New options in botanical interventions for menopause related hot flashes are always welcomed. Mung beans are familiar to many, as a dietary source of nutrients-whether in sprouted form or other use. It is typically consumed for its protein and essential fatty acid content. E. ulmoides is rich in polyphenolic compounds such as lignans and flavonoids. I look forward to continued research on botanical therapies for menopause symptoms and the ability to expand our treatment options.

References:

Garcia J, Gonzaga F, Tan D, et al. Use of a multi-botanical (Nutrafem) for the relief of menopausal vasomotor symptoms: a double-blind, placebo-controlled study. Menopause 2010; 17(2):303-308.

In each of the studies, women who consumed the highest dietary intake of soy had a lower risk for endometrial and ovarian cancers compared with the women who had the lowest intake.

Commentary: It is not surprising to see this report as we have seen previous observational studies with similar results, showing lack of endometrial proliferation, endometrial safety and/or reduced risk of endometrial cancer. Only one previous study that I’m aware of, did demonstrate that after 5 years, but not after one year or 3 years, who were given 150 mg per day of soy isoflavone tablets had an increased occurrence of endometrial hyperplasia (but no cases of atypical hyperplasia or endometrial cancer).[ii]

The mechanisms whereby soy appears to have an influence on lowering the risk of hormonal cancers, including breast, appear to be multiple. These include: through its ability to bind to certain estrogen receptors and actually have an estrogen blocking effect, raising sex hormone-binding globulin which decreases circulating estrogens, affecting selected enzyme pathways which result in anti-carcinogenic effects, direct tumor growth inhibition, and having antioxidant effects.

My advice: for most women, and for those who are not allergic to soy or have indigestion with soy products, I recommend 1-2 servings per day of the following soy foods: cooked soy beans, roasted soy nuts, soy milk, tofu, tempeh, edamame, tofu pate (my favorite).

[i] Myung S- K et al. Soy intake and risk of endocrine-related gynaecological cancer: A meta-analysis. BJOG 2009 Dec; 116:1697

[ii] Unfer V, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertility and Sterility 2004;82:145-148). 150 mg of soy isoflavones per day is above the average intake in an Asian diet (ranging from about 40-90 mg per day

The daily dose of herbal products given were 3 tablets containing 5400 mg of St. John’s wort standardized to contain 990 mcg hypericin, 9 mg hyperforin and 18 mg flavonoid glycosides. The daily dose of chaste tree berry was one tablet of an extract equivalent to 1000 mg of dry fruit. This was not a standardized extract. There was a matching placebo group. Participants recorded the severity of their PMS symptoms using the Abraham’s Menstrual Symptom Questionnaire.

The active treatment group was statistically superior to placebo for total PMS-like symptoms as well as subgroups of PMS depression and PMS food cravings.

Commentary: Based on previous research in PMS and chaste tree berry and PMS and St. John’s wort, as well as my clinical experience, it is not surprising that a combination of the two plants would be effective. PMS symptoms are common in regularly menstruating women, and it is also a common phenomenon in peri-menopausal women whose cycle and hormonal regularity is beginning to change. While this study evaluated a small group of women, it does address a significant population of women— those who are peri-menopausal and newly or still, experiencing PMS symptoms.

Reference:

Van Die M, Bone K, Burger H, et al. Effects of a combination of Hypericum perforatum and Vitex agnus-castus on PMS-like symptoms in late-perimenopausal women: Findings from a subpopulation analysis. J Alternative and Complementary Medicine 2009;15(9):1045-1048.

RESULTS: After 12 weeks of treatment, a non-significant difference in favor of the St. John’s wort group was observed in the daily hot flash frequency and the hot flash score. However, after those three months of treatment, women in the St. John’s wort group reported significantly better quality of life scores, and significantly fewer sleep problems compared to placebo.

Commentary: St. Johns wort research is expanding into the realm of use for perimenopause and menopause symptoms. Other recent studies have reported improvement in psychological, well-being and quality of life in symptomatic perimenopausal and menopausal women. In the current study, while not especially helpful for hot flashes, there was an improvement in quality of life scores and sleep problems. I commonly use St. Johns wort with black cohosh for women with hot flashes and mood issues during perimenopause and menopause. The research on each and even two studies using the combination of the two reveal that these two plants in combination are a premium option for perimenopausal and menopausal women with some of the most common of symptoms.

Reference

Al-Akoum M, Maunsell E, Verreault R, Provencher L, Otis H, Dodin S. Effects of Hypericum perforatum (St. John’s wort) on hot flashes and quality of life in perimenopausal women: a randomized pilot trial. Menopause. 2009 Mar-Apr;16(2):307-14

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 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

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.[i]

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.[ii]

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

[i] (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)

[ii] (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.)

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

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.

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.

The National Institutes of Health has one of the most well-accepted guidelines for women’s calcium intake:

Most people need to supplement to get enough calcium because we have reduced our dairy intake. Estimating dietary sources of calcium is an important first step, before deciding how much to augment in a pill. Not counting dairy or calcium-fortified foods, you get about 250 mg of calcium per day from our grains, seeds and vegetables. If you drink milk, calcium-fortified soy milk or OJ, you rack up an additional 300 mg per 1 cup serving. That’s 250 mg + 300 mg = 550 mg per day. Let’s say you’re 51, postmenopausal and not using estrogen. You’ll need an additional 950 mg to reach the goal of 1,500 mg per day. More is not better. Taking too much may not be good for your heart or other soft tissue and may inhibit mineral absorption.

But bone is not nourished by calcium alone. Vitamin D, is probably even more important than calcium. Other nutrients that can affect bone health include magnesium, manganese, boron, zinc, folic acid, vitamin B6 and vitamin K. These different nutrients are important in one or more of the following: bone density, bone architecture and/or bone strength.

Results – Blood pressure decreased similarly in both groups. HDL increased and LDL decreased significantly from baseline with Pycnogenol, but no significant differences were seen in HDL between the two groups, however, LDL was more significantly reduced in the Pycnogenol group. Perimenopause symptoms of depression, vasomotor symptoms, memory, anxiety, sexual function, and sleep all improved significantly (P< 0.001) with Pycnogenol as soon as one month after starting the treatment, in both severity and frequency. Most symptoms also improved with placebo, but not significantly.

Yang H-M, Liao M-F, Zhu S-Y, Liao M-N, Rohdewald P. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in perimenopausal women. Acta Obstetricia et Gynecologica. 2007;86:978-985

Commentary:

I was surprised to see this study, as I have never thought to use Pycnogenol in the treatment of perimenopause/menopause symptoms. The most common symptoms of perimenopause/menopause that I see in my practice are hot flashes, sweating, heart palpitations, fatigue, depression, decreased sexual function, insomnia and cognitive impairment. It’s imperative to have as many non-hormonal natural medicine options as possible, and making clinical decisions based on evidence based therapies is extremely helpful, enhancing our ability to help more women, more of the time. I’m pleased to be able to add Pycnogenol to my list of choices and will look forward to hopefully positive results.