With age comes many physiological changes; oftentimes, they’re dreaded changes. One example is menopause, which is associated with many uncomfortable side effects. Experienced largely in the latter years of a woman’s life, perimenopause can start as early as age 35, and it can last several years. Once a woman experiences her last period, menopause begins, which usually starts mid-to-late 40s—the median age of menopause for American women is about 47.5 years, and the United States has about 41.75 million women older than the age of 50, according to the North American Menopause Society (NAMS). Once this occurs, women enter into postmenopause. During these years, several things change in a woman’s body, and because a decline in estradiol levels occurs, perimenopausal, menopausal and postmenopausal women experience symptoms related to vasomotor instability, such as hot flashes and palpitations. Other symptoms include bone loss, mental decline, cold flashes, mood swings and many other unpleasant changes. Since 37.5 million U.S. women are at or near menopause, and 45.6 million are postmenopausal, according to NAMS; and hormone replacement therapy (HRT) isn’t always an attractive remedy, women are in search of effective remedies that can reduce symptoms and the risk for breast cancer and osteoporosis.

Ragged and Rooted

Among the many side effects that accompany menopause, fatigue, followed by anxiety and depression, plague many older women. Roots, such as the Peruvian root known as maca, have shown promise in helping women combat these symptoms, as well as others. Maca was found to be clinically useful in perimenopausal and menopausal women, as one study showed it benefits the production of sex hormones, enhanced sex drive, stimulated body metabolism, controlled body weight, increased energy, reduced stress, decreased depressant and improved memory.1 Preliminary findings published in Menopause confirmed these effects, showing six weeks of supplementing with 3.5 g/d of maca powder reduced psychological symptoms, including anxiety and depression, and lowered measures of sexual dysfunction in 14 postmenopausal women independent of estrogenic and androgenic activity.2

Phytoestrogens and Isoflavones

Phytoestrogens such as soy, red clover and plant lignans offer individual benefits during the different stages of menopause. Findings presented at the Ninth Annual AACR Frontiers in Cancer Prevention Research Conference in November 2010 showed among premenopausal women, the highest intake of isoflavones had a 30-percent decreased risk of stage I breast cancer, a 70-percent decreased risk of having a tumor larger than 2 cm, and a 60-percent decreased risk of having stage 2 breast cancer. These connections were not seen among postmenopausal women.

Isoflavones show promise not only in breast health, but on postmenopausal symptoms, too. A double blind prospective study randomly assigned 60 healthy postmenopausal women into two groups: 60 mg/d of isoflavones or placebo for three months. Fifty-one women finished the 12-week study.4 In women receiving 60 mg/d isoflavones, hot flashes and night sweats were reduced by 57 percent and 43 percent, respectively. The treatment did not change the levels of circulating estradiol or follicle-stimulating hormone. Immunohistochemical staining of endometrial and breast biopsy specimens revealed isoflavones did not affect expression levels of steroid receptors; estrogen receptors alpha, beta and betacx; progesterone receptors A and B; or the proliferation marker Ki67. No side effects on body weight or lipoprotein lipids were observed.

A whole-soy germ-based nutritional supplement containing natural S-equol, a compound resulting— when certain bacteria are present in the digestive tract—from the natural metabolism, or conversion, of daidzein, an isoflavone found in whole soybeans, reduced the frequency of moderate to severe hot flashes, reduced muscle and joint pain, and significantly inhibited bone breakdown in a study among postmenopausal U.S. women, according to peer-reviewed data presented as a poster presentation at the North American Menopause Society (NAMS) Annual Meeting.

Red clover also does its best to in the role of menopause management. In 2010, red clover-derived isoflavones (MF11RCE), similar to the roots mentioned above, were effective in reducing depressive and anxiety symptoms among postmenopausal women.5 A total of 109 postmenopausal women aged 40 or older were randomly assigned to receive two capsules/d of MF11RCE (80 mg of red clover isoflavones, Group A) or placebo (Group B) for 90 days. After a washout period of seven days, medication was crossed over and taken for 90 days more. After receiving the MF11RCE compound, anxiety and depression scores decreased significantly, with a 76.9-percent reduction in the total Hospital Anxiety and Depression Scale (HADS) score (76 percent for anxiety and 78.3 percent for depression); and an 80.6-percent reduction in the total Self-Rating Depression Scale (SDS) score. After placebo, total HADS (anxiety and depression subscale also) and total SDS scores also decreased significantly in comparison to baseline, but only equivalent to an average 21.7 percent decline.

Red clover seems to only work not on the brain, but on the bone, too. In one study, red clover isoflavones were found to be effective in reducing bone loss induced by ovariectomy, most likely by reducing of the bone turnover via inhibition of bone resorption.6 Bilateral ovariectomy was performed on female Wistar rats. One week after the operation, rats were treated with an oral dose of 20 and 40 mg/d of isoflavones for 14 weeks. Ovariectomy reduced bone mineral content, femoral weight, femoral density, mechanical strength of the tibia and increased the levels of bone-specific alkaline phosphatase in the serum and the number of osteoclasts in the femur sections compared with sham operated controls. Treatment with isoflavones significantly increased bone mineral content, mechanical strength of the tibia, femoral weight, femoral density and prevented the rise of serum alkaline phosphatase levels. In addition, the treatment with isoflavones significantly reduced the number of osteoclasts compared with the ovariectomized control rats.

A second root—Pueraria mirifica (PM)—also helps with vaginal dryness. A study published inMenopause found PM (as Puresterol®, from Bio-Botanica) showed estrogenicity on vaginal tissue by alleviating vaginal dryness symptoms and dyspareunia, and improving signs of vaginal atrophy, and restoring the atrophic vaginal epithelium in healthy postmenopausal women.3

Separately, a red clover preparation in dosages amenable to clinical practice improved ovariectomized -induced osteoporosis, with researchers noting a mild metabolic alkalosis might further synergize some therapeutic aspects.7 A quality-controlled red clover extract (RCE) standardized to contain 40-percent isoflavones by weight (genistein, daidzein, biochanin A and formononetin presented as hydrolyzed aglycones) together with a modified alkaline supplementation on bone metabolic and biomechanical parameters was used in an experimental model of surgically induced menopause. Rats were randomized into four groups: Group A represented normal rats (sham operated) while three other groups were ovariectomized and fed for three months: standard food (group B), 6 mg/kg/d food mixed with RCE (Group C), or given 6 mg/kg/d of RCE plus 16 mg of a modified alkaline supplementation (BP) (group D). The animals were killed 90 days after surgery. As compared to group B, RCE or RCE + BP treatments significantly increased estradiol levels, and mitigated the weight loss of the uterus and improved maximum load of the femoral neck. Osteocalcin level showed more than a 65-percent increase in group B, but both RCE and RCE + BP treatments prevented such abnormality with a significantly better result in RCE + BP group ,which virtually normalized such parameter as well as urinary excretion of DPD. Group C and D reduced the more than 20-percent loss of BMD and bone mineral content/body weight ratio observed in untreated post-ovariectomy group. Untreated ovariectomy caused about a 48-percent decrease of cancellous bone mass in the femoral neck, while this abnormality was prevented at similar extent by both RCE and RCE + BP treatments. Ovariectomy showed an 80-percent increase of bone alkaline phosphatase (BALP) level, but both RCE and RCE + BP treatments significantly mitigated such variable. The BALP decrease yielded by the combined RCE + BP treatment was statistically lower than RCE alone.

Plant lignans, although not an isoflavone like soy and red clover, exert weak estrogen-like activity after the body converts them into human lignans—mainly enterolactone. Lignans are able to make up for deficiencies when estrogen levels are low in the body, and are able to reduce the activity of estrogen; and similar to soy, they too play a role in breast health. A cohort study that included 29,785 women, ages 50 to 64 years, between 1993 and 1997, reported a tendency toward a lower risk for breast cancer with higher concentrations of enterolactone, which was restricted almost entirely to ERalpha-negative breast cancer.8 Finnish researchers also examined the association between serum enterolactone and risk of breast cancer, concluding, “Serum enterolactone level was significantly inversely associated with risk of breast cancer.”9

Within the same class of phytoestrogens is genistein, an isoflavone that serves as a very weak phytoestrogen that has shown promise in many peri- and postmenopausal women. Italian researchers compared the effects of genistein, estrogen-progestogen therapy (EPT) and placebo on hot flushes and endometrial thickness in postmenopausal women.10 A total of 90 healthy, postmenopausal women, 47 to 57 years of age, were randomly assigned to receive continuous EPT (n=30; 1 mg 17 beta-estradiol combined with 0.5 mg norethisterone acetate), the phytoestrogen genistein (n=30; 54 mg/d) or placebo (n=30) for one year. Daily flushes reduced significantly by 22 percent after three months, 29 percent after six months and 24 percent after 12 months of genistein treatment compared with placebo. Flush score decreased by 53 percent after three months, 56 percent after six months and 54 percent after 12 months of EPT, as compared with placebo. No side effect was observed on the uterus of the participants.

A placebo-controlled, double blind study presented by James Elliott at the Ninth International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment meeting in Washington, conducted in collaboration with KGK Synergize Inc., London, Ontario, randomized 84 healthy postmenopausal women to receive either geniVida ®(from DSM), pure genistein or a placebo. After 12 weeks, the women on geniVida had a 51-percent reduction on hot flashes and night sweats compared to only 27 percent for the women in the placebo.

In 2002, researchers performed a randomized, double blind, placebo-controlled study to evaluate and compare HRT with the effect of the phytoestrogen genistein on bone metabolism and BMD in postmenopausal women.11 A total of 90 healthy ambulatory women, 47 to 57 years old, with a BMD at the femoral neck of less than 0.795 g/cm2 were randomly assigned to receive continuous HRT for one year, 54 mg/d of genistein or placebo after a four-week stabilization on a standard fat-reduced diet. Genistein treatment significantly reduced the excretion of pyridinium cross-links at six months and 12 months, unlike the placebo. A similar and not statistically different decrease in excretion of pyridinium cross-links was also observed in the postmenopausal women randomized to receive HRT. Genistein markedly increased serum bone-specific ALP (B-ALP) and osteocalcin (bone Glaprotein [BGP]) either at six months or at 12 months. Postmenopausal women treated with HRT had, in contrast, decreased serum B-ALP and BGP levels either at six months or 12 months. Furthermore, at the end of the experimental period, genistein and HRT significantly increased BMD in the femur and lumbar spine

Herbal Help

Black cohosh (Actaea racemosa L), a member of the buttercup family, along with St. John’s wort and a few other herbal remedies, also thwarts menopausal side effects such as hot flashes, depression and anxiety. A 2010 systematic search of three databases was conducted, revealing preparations containing black cohosh improved menopausal symptoms overall by 26 percent; there was, however, significant heterogeneity between these trials.13

Another benefit to black cohosh is its safety profile. A number of clinical studies using Remifemin, a standardized extract used in Europe as an alternative to HRT, have demonstrated efficacy for the alleviation of menopausal complaints.14 The safety profile of black cohosh is positive, with low toxicity, few and mild side effects, and good tolerability, according to the studies.

In contrast, a randomized, double blind, placebo-controlled, parallel group trial examined the efficacy and tolerability of Cimicifuga racemosa (black cohosh) extract for the treatment of anxiety disorder due to menopause, and it didn’t fare well.15 Subjects were randomized to therapy with either pharmaceutical-grade black cohosh extract (n=15) or placebo (n=13) for up to 12 weeks. There was neither a significant group difference in change over time in total HAM-A scores, nor a group difference in the proportion of subjects with a reduction of 50 percent or higher in baseline HAM-A scores at study end point (P=0.79). There was a significantly greater reduction in the total Green Climacteric Scale (GCS) scores during placebo (versus black cohosh; P=0.035), but no group difference in change over time in the GCS subscale scores or in the PGWBI (P=0.140). One subject (3.6 pecent) taking black cohosh discontinued treatment because of adverse events. Overall, researchers found no statistically significant anxiolytic effect of black cohosh versus placebo. However, small sample size, choice of black cohosh preparation, and dosage used may have been limiting factors producing negative results.

St. John’s wort has a reputation in effectively fighting off vasomotor symptoms. A study published in the March 2010 issue of Menopause included 100 women, with a mean age of 50.4 years, treated with St. John's wort extract or placebo for eight weeks.16 The difference in duration of hot flashes between the groups was not significant on the fourth week of intervention (P=0.27); however, it was statistically significant between the two groups on the eighth week of treatment (P<0.001). The fall-off in frequency of hot flashes on the fourth and eighth weeks of intervention was more evident in women receiving St. John's wort, and the differences between groups were statistically significant (P=0.005 and P<0.001, respectively). When both study groups were compared, the decrease in the severity of flashes in women who received St. John's wort was more evident on the fourth and eighth weeks (P=0.004 and P<0.001, respectively).

These results coincide with a pilot double blind, randomized clinical trial conducted one year prior.17 A total of 47 symptomatic perimenopausal women aged 40 to 65 years who experienced three or more hot flashes a day were randomly assigned to receive ethanolic St. John's wort extract (900 mg TID) or placebo. The women were asked to keep a daily diary during the week before randomization and during the week before the three-month follow-up to record hot flash frequency and intensity. After 12 weeks of treatment, a non-significant difference favoring the St. John's wort group was observed in the daily hot flash frequency and the hot flash score. After three months of treatment, compared with the placebo group, women in the St. John's wort group reported significantly better menopause-specific quality of life and significantly fewer sleep problems. “Hypericum perforatum may improve quality of life in ways that are important to symptomatic perimenopausal women, but these results need to be confirmed by a larger clinical trial,” the researchers said.

Interestingly, during the North American Menopause Society (NAMS)/Utian Translational Science Symposium on Soy and Soy Isoflavones, held Oct. 9 to 10, 2010, a working group of faculty and panelists composed of clinical and research experts in the fields of women's health and botanicals met to cover the latest evidence-based science on isoflavones as they affect menopausal symptoms, breast and endometrial cancer, atherosclerosis, bone loss and cognition.12 The group reported: “From the hundreds of studies reviewed in this report, there are mixed results of the effects on midlife women. Soy-based isoflavones are modestly effective in relieving menopausal symptoms; supplements providing higher proportions of genistein or increased in S-equol may provide more benefits. Soy food consumption is associated with a lower risk of breast and endometrial cancer in observational studies. The efficacy of isoflavones on bone has not been proven, and the clinical picture of whether soy has cardiovascular benefits is still evolving. Preliminary findings on cognitive benefit from isoflavone therapy support a ‘critical window’ hypothesis wherein younger postmenopausal women derive more than older women.”
Black cohosh and St. John’s wort have garnered a lot of attention in the menopause market; but a couple of lesser known herbal combos have also lent promising results. Genopause®, an Ayurvedic formulation of Tinospora cordifolia, Asparagus racemosus, Withania somnifera and Commiphora mukulfrom Gencor Nutrients, was examined in an unpublished study for its neuropsychophysiological affect on menopausal women, aged 40 to 60 years, who ended their menstrual cycle one year prior. They were randomized in a double blind, placebo-controlled manner into two groups: Group 1 administered a placebo to 70 menopausal females for six months. Group 2 gave 86 menopause females the organic extract of 150 mg of Tinospora cordifolia, 200 mg of Asparagus racemosus, 200 mg of Withania somnifera and 450 mg of Commiphora mukul in effective doses continuously for six months. Hot flushes, parethesia, insomnia, nervousness, melancholia, vertigo, weakness, anthelia and myalgia, headaches and palpitations improved considerably in the treatment group after six months. Depressive behavior also improved, as well as a decrease in body fat and positive chances in cholesterol levels in the herbal treatment group.

Another unpublished study was conducted on a different herbal remedy, EstroG-100™ (from SunBio)—Cynanchum wilfordii, Phlomis umbrosa and Angelica gigas­. A three-month, randomized, double blind, placebo-controlled clinical trial was performed for 12 weeks with 61 pre-, peri- and postmenopausal non-Asian American women, who were randomly allocated to either the EstroG-100 group (n=31) or placebo group (n=33). The mean Kupperman Menopause Index (KMI) score was significantly reduced in the EstroG-100 group from 29.45±7.39 at baseline to 13.62±7.61 at week six and to 11.31±5.78 at week 12, while the placebo group showed changes from 29.16±6.55 at baseline to 23.31±8.96 at week six and to 23.66±7.68 at week 12. The improvement was statistically significant in comparison with the two groups (P<0.01). EstroG-100 showed statistically significant improvement in menopausal symptoms such as hot flush and night sweats, paresthesia, insomnia, nervousness, melancholia, vertigo, fatigue, rheumatic pain and vaginal dryness compared to placebo. No adverse effects were reported with EstroG-100. Weight, biochemical safety markers as well as serum hormone levels all failed to show any statistically significant changes. Additionally, in a binding affinity test showed EstroG-100 and black cohosh had no binding affinity to ER-alpha and ER-beta.

From the Vine

Resveratrol is popular for anti-aging and heart health, but it also exerts estrogenic effects. In 2007, Taiwanese researchers investigated resveratrol’s potential for therapy of osteoporosis.18 They found resveratrol exhibited bone-protective effects equivalent to those exerted by HRT, as well as decreased the risk of breast cancer in in vivo and in vitro models. Forkhead proteins were essential for both effects of resveratrol. The bone-protective effect was attributable to induction of bone morphogenetic protein-2 through Src kinase-dependent estrogen receptor activation, and FOXA1 is required for resveratrol-induced estrogen receptor-dependent bone morphogenetic protein-2 expression. The tumor-suppressive effects of resveratrol were the consequence of Aktinactivation-mediated FOXO3a nuclear accumulation and activation.

Additionally, the University of Connecticut randomly assigned 24 pre- and 20 postmenopausal women to consume 36 g/d of a lyophilized grape powder (LGP; 92 percent carbohydrate and rich in flavans, anthocyanins, quercetin, myricetin, kaempferol and resveratrol) or placebo for four weeks.19 After a three-week washout period, subjects were assigned to the alternate treatment for an additional four weeks. Plasma triglyceride concentrations were reduced by 15 percent and 6 percent in pre- and postmenopausal women, respectively (P<0.01) after LGP supplementation. In addition, plasma low-density lipoprotein (LDL) cholesterol, and apolipoproteins B and E were lower due to LGP treatment (P<0.05). Further, cholesterol ester transfer protein activity was decreased by approximately 15 percent with intake of LGP (P<0.05). In contrast to these beneficial effects on plasma lipids, LDL oxidation was not modified by LGP treatment. However, whole-body oxidative stress as measured by urinary F(2)-isoprostanes was significantly reduced after LGP supplementation. LGP also decreased the levels of plasma tumor necrosis factor-alpha (TNF-a), which plays a major role in the inflammation process. Through alterations in lipoprotein metabolism, oxidative stress and inflammatory markers, LGP intake beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women.

Menopause can be a long road; and it can seem even longer without symptomatic relief. Fortunately, these ingredients provide a good starting point for women under fire. But in order to expand its offerings and its science, the menopausal market needs to continue researching new and mainstay ingredients for their safety, toxicity, efficacy and innovation.