Natural Ingredients Address Menopausal Symptoms

When a society regards youth as virile, healthy and beautiful, it is natural, then, that the quest for staying forever young is rampant. From anti-aging beauty products, anti-wrinkle quick fixes, cosmetic surgery that takes “years off the face,” to a general shunning or even denial of the changes, aches and pains old age delivers, it is no surprise the thought of growing old is draped with hesitation and dread. As Roman philosopher Cicero put it: “As I give thought to the matter, I find four causes for the apparent misery of old age: first, it withdraws us from active accomplishments; second, it renders the body less powerful; third, it deprives us of almost all forms of enjoyment; fourth, it stands not far from death.”

For women, age brings with it an increased risk for chronic diseases, as well as the end of the fertile phase of life and the shutting down of the reproductive system. According to the North American Menopause Society (NAMS), “Menopause is a natural biologic event, not a disease or an estrogen deficiency disease. ... Menopause is a psychosocial passage.”

The term menopause comes from the Greek words “month” and “cessation” and refers to a woman’s last menstrual period. Usually this occurs when the ovaries no longer make enough estrogen to produce and support a menstrual cycle; but, other reasons can induce menopause such as medical intervention, surgical removal of both ovaries or cancer treatments. Natural menopause kicks in around the age of 52, although women can experience it between the ages of 40 and 55 years. Premature menopause occurs in women less than 40 years old; perimenopause is the time during or around menopause (usually during a woman’s 40s and sometimes in her later 30s), when the symptoms most associated with menopause occur. During this time, estrogen levels are erratic; they can become highly elevated or stoop as low as 10 percent of normal reproductive highs. Simultaneous life stresses associated with midlife and the effects of aging can also increase the amount of distress menopause changes can cause.

As the Baby Boomer generation ages, an unprecedented number of women have become postmenopausal; an estimated 6,000 U.S. women reach menopause every day (more than 2 million per year, NAMS noted). Every woman is affected by menopause differently, both physically and mentally. One woman may consider it a “medical condition” or a negative sign of old age; another may view the change as a natural process that requires no medical intervention and is a liberating period that ends the concern of pregnancy and anxiety about menstruation. Women who experience induced menopause usually have a greater need for treatment to control the associated symptoms than women who undergo natural menopause. Many women who have natural menopause report no physical changes during the perimenopausal years except irregular menstrual periods, which eventually end when menopause is reached. Other women experience hot flashes, vaginal dryness, difficulty sleeping, mood changes and other discomforts. Associated health-related risks include osteoporosis and a higher prevalence of cardiovascular risk factors.

Lifestyle changes, such as exercise, diet modification, weight management and not smoking, can help reduce menopause-related discomforts. In tandem with a healthy lifestyle, dietary supplements and alternative therapies are increasingly being used to relieve symptoms associated with menopause, especially since studies have raised concerns regarding the safety of hormone replacement therapy (HRT). In a national study of 4,975 women aged 35 to 64 years old, regarding their attitudes toward menopause and concerns about the menopause experience, 71 percent said they experienced at least one menopause symptom. The most common was hot flashes (84 percent), followed by mood swings (53 percent) and night sweats (52 percent).¹ About 40 percent of respondents felt comfortable choosing over-the-counter (OTC) or herbal remedies to treat their menopause discomforts; soy products (41 percent) and vitamin E were the most commonly discussed and tried products. The most important factor for choosing a treatment: safety (54 percent), symptom relief (39 percent) and few side effects (29 percent).

Flash Forward

The most common menopause-related discomfort is hot flashes (or hot flushes). They are thought to be the result of changes in the hypothalamus, the part of the brain that regulates the body’s temperature. If the hypothalamus senses the woman is too warm, it starts a chain of events to cool her down. Blood vessels near the surface of the skin begin to dilate, increasing blood flow to the surface in an attempt to dissipate body heat. It may also make a woman perspire to cool the body. An increased pulse rate and a sensation of rapid heart beating may also occur. Some hot flashes are followed by a cold chill. For women with frequent hot flashes, clinicians may suggest isoflavone supplements at about 40 to 80 mg/d or whole soy foods. Isoflavones are well-known phytoestrogens, active substances derived from plants that have a weak-estrogen-like action. Isoflavones are commonly found in soy and red clover. Lignans have also been identified as phytoestrogens.

Isoflavones from soy have been shown to provide several benefits ranging from heart health to maintaining good bone health in postmenopausal women. In a double blind prospective study, 60 postmenopausal women were randomly assigned to receive 60 mg/d of isoflavones (from soybean) or placebo for three months.² In the women who received isoflavones daily, hot flashes and night sweats were reduced by 57 percent and 43 percent, respectively. The study implied isoflavones could be used to relieve acute menopausal symptoms. A study from the Beth Deaconess Medical Center in Boston found consuming soy nuts three or four times throughout the day, along with therapeutic lifestyle changes, decreased incidence of hot flashes and improved menopausal symptoms.³ Research from Harvard Medical School found a dietary supplement rich in the soy isoflavone daidzein could reduce the incidence of hot flushes by 52 percent.⁴ Researchers gave 147 post menopausal women a placebo, 40 mg/d or 60 mg/d of daidzein-rich isoflavone-aglycone (DRI). Researchers found the number of hot flushes in the group that received the lower dose of isoflavones was reduced by 52 percent, women receiving the higher dose experienced a 51-percent reduction, and the placebo group reported a 39-percent reduction in hot flushes.

The efficacy of soy isoflavones to ease symptoms of menopause, specifically hot flashes, continues to be debated. A study published in Maturitas found supplementation of soy isoflavones does ease hot flushes.⁵ A meta-analysis from Griffith University School of Medicine reviewed 17 randomized, controlled studies and found isoflavone supplementation was associated with a 20 percent reduction in the amount of flushes in women experiencing 10 or more flushes every day.⁶ A study out of Italy confirmed in a larger population study of postmenopausal women that taking 56 mg/d of phytoestrogen aglycone genistein (as Bonistein®, from DSM Nutritional Products) can reduce the number and severity of hot flushes without exerting adverse effects on the endometrium.⁷ A total of 389 women were randomly assigned to receive genistein or placebo; the effect of the genistein was apparent after the first month and reached its peak after 12 months (56.4 percent reduction in the number of hot flushes). Researchers concluded genistein is effective on vasomotor symptoms and decreases the number and severity of hot flushes and night sweats.

Postmenopausal osteoporosis is said to be the result of a sharp decrease in estrogen levels and leads to an increased rate of bone remodeling.^8,9,10 Observational studies suggest postmenopausal Asian women who consume diets high in isoflavones have a lower rate of fracture than other groups.^11,12 A randomized, double blind trial conducted at three university medical centers in Italy studied 389 postmenopausal women with a bone mineral density (BMD) of less than 795 g/cm² at the femoral neck and no significant comorbid conditions. Patients took either a placebo or 54 mg of genistein daily for 24 months. Results showed BMD had increased in genistein recipients and decreased in placebo recipients at the anteroposterior lumber spine.

On the opposite end of the spectrum, a Cochrane Database System Review concluded there is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments (including dietary soy, soy extracts, red clover extracts and other types of phytoestrogens).¹³ A systemic review from the University of Minnesota evaluated research from the Cochrane Library and Medline from 1966 to March 2004 and, based on the available evidence, found phytoestrogens from soy and red clover did not improve hot flushes.¹⁴

However, a report published in Menopause said concluding isoflavone supplements do not significantly reduce hot flash symptoms may be incorrect, adding the lack of discrimination between individual isoflavones contained in heterogeneous isoflavone mixtures from differing sources can be misleading when designing studies, interpreting results and conducting reviews.¹⁵

It appears the conflicting messages are not affecting the interest in soy products for health. The Packaged Facts report “Soy Foods and Beverages” estimated total retail sales of soy products reached $2.1 billion in 2007, up 7 percent from 2006. The report also noted one out of every five consumers report they believe consuming soy-based foods and beverages provides, heart-health function (16 percent), cholesterol-lowering properties (11 percent) and potential for menopause symptom relief (10 percent).

Isoflavones can come from other plant sources as well. Red clover extract, for example, contains genistein and daidzen, which makes it a popular option for easing menopausal changes. And much like soy, evidence is inconsistent on whether it is effective in helping menopausal hot flashes.^{16,17,18,19,20} In a 12-week double blind, controlled trial of 30 postmenopausal women, 80 mg/d was found to significantly reduce hot flashes.²¹ A randomized, double blind study from Guayaquil, Ecuador, supported the notion that 80 mg/d of red clover supplementation in post menopausal women significantly decreased menopausal symptoms (baseline:27.2+/-7.7; after isoflavones: 5.9+/-3.9; after placebo: 20.9=/-5.3, P<0.05).²²

One of the largest studies (n=252), however, discredited the potential of red clover and its effects on menopause symptoms.²³ Known as the Isoflavone Clover Extract study, researchers revealed the reduction of daily hot flashes from red clover extract (as Promensil® and Rimostil®, from Novogen) at 12 weeks were similar to placebo; they also noted there was a biological effect from Promensil but not a clinically important one on hot flashes.

Lignans are one the three main groups of plant compounds classified as phytoestrogens. A study by Medicus Research, on the effects of 7-hydroxymatairesinol (7-HMR) (as HMRlignan™, from Linnea) revealed the naturally occurring plant lignan from the Norway spruce (Picea abies) possesses the ability to cut down hot flashes by 53 percent in postmenopausal women.²⁴ The eight-week controlled study of 20 menopausal women compared two doses of 7-HMR (25 mg/d and 50 mg/d). At baseline, both groups had a similar mean number hot flashes per day; by week four, the 25-mg group’s mean number of hot flashes was not significant but the 50-mg group’s was reduced to 2.7 per day. By week eight, the 25-mg group experienced a reduction of 3.7 hot flashes per day and the 50 mg group experienced 2.0 reductions.

The root Kwao Krua or Pueraria mirifica (PM), from areas in Northeastern Thailand and Myanmar, contains a number of isoflavones, such as estrogenic phenol miroestrol. It has been shown to have some benefit for menopausal symptoms. A randomized, double blind study investigated 71 postmenopausal women who randomly received 20, 30 or 50 mg/d of PM or placebo for 24 weeks.²⁵ Mean vaginal dryness in the PM group decreased after 12 weeks of treatment, and the vaginal maturation index increased from 46:43:11 to 11:65:24 after 24 weeks. Researchers from the Hat Yai Regional Hospital, Songkhla, Thailand, found PM relatively alleviated climacteric symptoms such as hot flushes and night sweats in perimenopausal women; however optimal doses need to be clinically assessed.²⁶ The same researchers compared PM to conjugated equine estrogen (CEE), and found the root possesses a similar estrogenic effect as CEE and can alleviate menopause-related changes.²⁷ In another study, they looked at the efficacy and safety of PM and found it to be relatively safe for the alleviation of climacteric symptoms; however, data is insufficient to draw definite conclusions on its estrogenic effect.²⁸

One of the most accepted herbal supplements for menopause is black cohosh, a member of the buttercup family native to the rich woods of North America and grown commercially in Europe. It has been found to possess an estrogen-like action, binding to estrogen receptors and suppressing the luteinizing hormone. In Germany, black cohosh preparations are commonly used to improve symptoms such as hot flashes, depression and sleep disturbance and is covered by a positive monograph of the German Commission E, which allows such products to be labeled for “premenstrual discomfort, dysmenorrhea or climacteric (menopausal) neurovegetative ailments.” Its acceptance was fueled when German researchers found black cohosh produced an effect on serum concentrations of pituitary hormone levels, including a significant and selective reduction of luteinizing hormone.²⁹ Hot flashes have been linked to a significant spike in the release of luteinizing hormone. Another German study failed to identify a single chemical component of black cohosh (as Remifemin®, from Enzymatic Therapy) responsible for the luteinizing hormone suppressing activity, suggesting synergistic effects from several chemical fractions were involved in the biological activity.³⁰ Another German study propelled black cohosh into the spotlight after researchers found 80 percent of the 629 women who underwent six to eight weeks of treatment with black cohosh had improvements in hot flashes, fatigue, irritability and vaginal dryness.³¹ At eight weeks, 50 percent of women were symptom-free.

More recent studies on the herb have also indicated benefits. A 12-week double blind, placebo-controlled trial of 304 women with menopausal symptoms found black cohosh was more effective than placebo.³² The researchers noted black cohosh’s effect size was 0.03 to 0.05 Menopause Rating Scale units, which is similar to recent HRT study results and can be considered clinically relevant. A three-month study of 120 menopausal women comparing black cohosh to fluoxetine (as Prozac, from Eli Lilly) found black cohosh (Klimadynon®, from Bionorica; Menofem®, from AG Natural Health) reduced the incidence of hot flashes more effectively than fluoxetine; however, the drug was more effective than the herb for menopause-related mood changes.³³ Another study found black cohosh reduced overall menopausal symptoms to the same extent as a drug and might reduce vaginal thinning, does not affect the cells in an estrogen-like manner, and may protect the bones.³⁴ A substantial study of 244 participants compared black cohosh against the synthetic hormone tibolone and found them equally effective in treating menopause symptoms.³⁵

Systematic reviews have also shed light on the herb’s effectiveness and safety. A review from the University of Exter, United Kingdom, concluded black cohosh is a safe herbal medicine; however, a slight risk of mild transient adverse events are rare, but may occur if taken for a limited amount of time.³⁶ A review from the University of Naples Federico II, Naples, Italy, investigated black cohosh’s efficacy by looking at data from Medline, Embase, Amed, Phytobase and Cochrane Library.³⁷ Investigation of double blind, randomized clinical trials revealed black cohosh did not consistently demonstrate an effect on menopausal conditions, and efficacy of the herb as a treatment is uncertain and further rigorous trials are warranted. A review out of Poland concluded 32 studies showed contradictory results and adverse symptoms are rare (5.4 percent), mild and reversible.³⁸

Mood Benders

In addition to the physiologic symptoms, such as hot flashes and night sweats, other commonly reported symptoms include psychological symptoms such as mood changes (increased sadness, depression and/or anxiety). Researchers combed through MEDLINE and EMBASE databases from 1966 to April 2006, as well as the Commission E reports and the German Regulatory Health Authority, looking for botanical and dietary supplements that were used for treatment of mood and anxiety disorders by middle aged peri- and postmenopausal women.³⁹ The authors concluded St. John’s wort (Hypericum perforatum) and black cohosh were the most useful in alleviating mood and anxiety changes during menopause; Asian ginseng holds promise but needs more research; kava “holds promise for decreasing anxiety but should be used carefully;” and Ginkgo biloba and valerian do not appear to reduce depression or anxiety in menopausal women.

The combination of St. John’s wort and black cohosh has been studied for its role in climacteric conditions and mood changes resulting from menopause. A study on the combination of the two herbs (Remifemin® plus, from Enzymatic Therapy) on Korean peri- or postmenopausal women revealed it was more effective in menopausal patients with mood complaints compared to the black cohosh monotherapy.⁴⁰ A double blind study of 301 women found the combination was significantly more effective than placebo for general menopause symptoms and depression.⁴¹

The Calming Horizon

During the SupplySide West 2007 show in Las Vegas, Mark Blumenthal from the American Botanical Council mentioned the possible 2008 introduction into the U.S. marketplace of Phytostrol N-ERr 731 (Muller-Goppingen, Germany), a Rhaponticum rhubarb root extract for menopause conditions. The herb has been available in Germany since 1993, and several trials have found a reduction in menopause symptoms based on its phystoestrogenic compound lindleyin. A study published in the 2007 issue of Menopause claimed rhubarb extract ERr 731 decreases anxiety and improves health state and general well-being in perimenopausal women.⁴² In a 12-week double blind, placebo-controlled trial of 109 women, researchers found the use of the extract could significantly reduces the occurrence and severity of climacteric complaints in perimenopause.⁴³

The blending of noted herbs for menopause conditions also holds promise. A combination product containing standardized extracts of black cohosh, dong quai, milk thistle, red clover, American ginseng and chaste-berry (as Phyto-Female Complex®, from SupHerb) offers relief of hot flashes and night sweats, and benefits sleep quality.⁴⁴ The subjects who took the complex experienced a 25-percent reduction of hot flashes and a 23-percent reduction in night sweats, versus 8-percent and 15-percent reductions revealed in the placebo group at the end of the second week. By the end of 12 weeks, the group taking the complex experienced a 73-percent reduction in hot flashes and a 69-percent reduction of night sweats, versus 38 percent and 29 percent, respectively.

New innovations in the menopause category are inspired by the traditions of indigenous people across the world. Maca has been used by the native people in Peru as a traditional remedy to treat various female-related disorders. A pilot study on early postmenopausal women found a non-hormonal pre-galatinized organic maca preparation(as Maca-Go®, from Nature Corp.) exhibited hormone-balancing effects, leading researchers to suggest the herb may reduce the discomfort experienced by women in the early postmenopausal stage.⁴⁵ Traditional Chinese Medicine (TCM) has also been studied as a possible replacement for HRT. Researchers studied 31 peri- and postmenopausal Dutch women in a double blind and double-dummy randomized, placebo-controlled pilot trial.⁴⁶ Regarding hot flashes, placebo reduced hot flashes 30 percent, TCM had a 29 percent higher average score, while HRT had a 50 percent average score. Other studies have not been as successful in proving the effectiveness of TCM.^47,48

A new botanical ingredient fresh on the menopause market is a particular female hop extract standardized in prenylflavonoids including 8-prenylnaringenin (8-PN) (as Lifenol®, from Naturex). A racemic 8-PN was also recently studied in Leiden, Netherlands; researchers concluded single oral doses of up to 750 mg were well tolerated, and a decrease in LH serum concentrations as a result of the 8-PN provided systemic endocrine effects in postmenopausal women.⁴⁹

A standardized French maritime pine bark extract (as Pycnogenol®, from Horphag) has been studied for its effects in reducing climacteric symptoms. One hundred fifty-five participants took part in a double blind, placebo-controlled study and were given either 200 mg/d Pycnogenol or placebo.⁵⁰ The researchers concluded all climacteric symptoms improved as evaluated by the Women’s Health Questionnaire (WHQ), and the antioxidative status increased as well.

Vitamin E has also made its way into the category. A study out of the Tarbiat Modarres University, Tehran, Iran reported vitamin E (400 IU/d) was more effective than placebo in the treatment of hot flashes.⁵¹ Another study conducted at the Mayo Clinic and May Foundation found in 120 breast cancer survivors given vitamin E (800 IU/d) a reduction in hot flash frequency (25 percent versus 22 percent from the placebo group). The researchers noted the clinical magnitude of the hot flash reduction was marginal.⁵²

As more women turn to natural alternatives for easing their passage into menopause, soy, red clover and black cohosh will continue to be researched and evaluated to defend their position in this women’s health category. The trend of “what’s old is new again” will also drift into the category, as traditional herbal supplements are further studied and evidence emerges on the benefits of certain vitamins and nutrients. Candidates such as vitamin E, American ginseng, evening primose oil, dong quai, ginkgo biloba, chaste-berry, alfalfa and royal jelly could potentially be revisited as possible nutrients for easing menopausal conditions.

References on the next page.

References for "Natural Ingredients Address Menopausal Symptoms"

1.      Singh B. et al. “Menopausal issues: a national probability sample of U.S. women.”Altern Ther Health Med.2007 May June;13(3):24-29.2.      Cheng G et al. “Isoflavone treatment for acute menopausal symptoms.” Menopause.2007 May-June;12(3 Pt 1):468-73. 3.      Welty FK et al. “The association between soy nut consumption and decreased menopausal symptoms.” J Womens Health (Larchmt).2007 Apr;16(3):361-9.4.      Khaodhiar L et al. “Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women.” Menopause; 2008 Jan;15(1):125-134.5.      Nahas EA et al. “Efficacy and safety of a soy isoflavone extract in postmenopausal women: a randomized, double-blind, and placebo-controlled study.” Maturitas.2007 Nov 20;58(3):249-58.6.      Howees, LG et al. “Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis.” Maturitas. 2006 Oct;55(3):203-211.7.      Rosario, DA et al. “Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study.” Menopause. 2007;14(4):1-8.8.      Albright, F et al. “Postmenopausal osteoporosis.” JAMA. 1941; 116:2465-74.9.      Schot LP et al. “Sex steroids and osteoporosis: effects of deficiencies and substitutive treatments.” J Steroid Biochem Mol Biol. 1990;37:167-8210.  Seeman E. “Estrogen, androgen and the pathogenesis of bone fragility in women and men.” Curr Osteoporos Rep. 2004;2:90-6.11.  Setchell KD et al. “dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies.”Am J Clin Nutr.2003; 78:593S-609S.12.  Messina M et al. “Skeletal benefits of soy isoflavones: a review of the clinical trial and epidemiologic data.” Curr Opin Clin Nutr Metab Care. 2004; 7:649-58.13.  Lethaby AE et al. “Phytoestrogens for vasomotor menopausal symptoms.” Cochrane Database Syst Rev. 2007 Oct;4:CD001395.14.  Krebs EE et al. “Phytoestrogens for treatment of menopausal symptoms: a systematic review.” Obstet Gynecol. 2004 Oct;104(4):824-36.15.  Williamson-Hughes PS et al. “Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies” Menopause. 2006;13(5).16.  Baber RJ et al. “Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women.” Climacteric.1999;2:85-92.17.  KnightDC et al.”The effect of Promensil, an isoflavone extract, on menopausal symptoms.” Climacteric. 1999;2:79-84.18.  van de Weijer P et al. “Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo.” Maturitas. 2002;42:18.19.  Tice JA et al. “Phytoestrogen supplements for the treatment of hot flashes: The Isoflavone Clover Extract (ICE) Study.” JAMA. 2003;290:207-214.20.  Hidalgo LA et al. “The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: A randomized, double-blind, placebo-controlled study.” Gynecol Endocrinol. 2005;21:257-264.21.  van de Weijer P et al. “Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo.” Maturitas. 2002;42:18.22.  Hidalgo LA et al. “The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: A randomized, double-blind, placebo-controlled study.” Gynecol Endocrinol. 2005;21:257-264.23.  Tice JA et al. “Phytoestrogen supplements for the treatment of hot flashes: The Isoflavone Clover Extract (ICE) Study.” JAMA. 2003;290:207-214.24.  Udani J et al. “7-Hydroxymatairesinol (7-HMR) New pharmacokinetic data and effect on enterolactone metabolites and hot flashes in menopausal women.” Scripps Integrative Medicine 5^th Annual Natural Supplements Conference. Jan 2008. 25.  Manonai J et al. “Effect of Pueraria mififica on vaginal health.” Menopause. 2007 Sep-Oct;14(5):919-24.26.  Chandeying V et al. “Efficacy and safety of Pueraria mirifica (Kwao Kruea Khao) for the treatment of vasomotor symptoms in perimenopausal women: Phase II study” J Med Assoc Thai.2004 Jan;87(1):33-40.27.   Chandeying V et al. “Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: pase II study.” J Med Assoc Thai.2007 Sept;90(9):1720-628.  Chandeying V. et al. “Challenges in the condut of Thai herbal scientific study: efficacy and safety of phytoestrogen, pueraria mirifica (Kwao Keur Kao), phase 1, in the alleviation of climacteric symptoms in perimenopausal women.” J Med Assoc Thai. 2007 Jul; 90(7):1274-80.29.  Jarry H et al. “Studies on the endocrine effects of the contents of Cimicifuga racemosa:” Planta Med. 1985 Feb;51(1):46-4930.  Düker Em et al. “Effects of extracts from Cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats.” Planta Med. 1991 Oct;57(5):420-4.31.  Stolze H. An alternative to treat menopausal complaints. Gyne 1982; 3:14 - 16.32.  Osmers R et al. “Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms.” Obstet Gynecol. 2005;105:1074-1083SS33.  Oktem M et al. “Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial.” Adv Ther. 2007 Mar-Apr;24(2):448-6134.  Wuttke Wet al. “Effects of black cohosh (Cimicifuga racemosa) on bone turnover,vaginal mucosa, and various blood parameters in postmenopausal women: a double-blind, placebo-controlled, and conjugated estrogens-controlled study.” Menopause. 2006;13:185-196.35.  Bai W et al. “Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: A randomized, double blind, parallel-controlled study versus tibolone.” Maturitas. 2007 Jun 21. 36.  Huntley A et al. “A systematic review of the safety of black cohosh.” Menopause. 2003 Jan-Feb;10(1):58-65.37.  Borrelli F et al. “Black cohosh for menopausal symptoms: A systematic review of its efficacy.” Pharmacol Res. 2008 June 8. [E pub ahead of print]38.  Kanadys WM et al. “Efficacy and safety of Black cohosh in the treatment of vasomotor symptoms—review of clinical trials.” Ginekol Pol. 2008 Apr; 79(4):287-96.39.  Geller SE et al. “Botanical and dietary supplements for mood and anxiety in menopausal women. Menopause. 2007;14(3):541-549.40.  Chung D-J et al. “Black cohosh and St. John’s Wort (GYNO-plus®) for climacteric symptoms.” Yonsei Med J. 2007;48(2):289-294.41.  Uebelhack R et al. “Black cohosh and St. John's wort for climacteric complaints: a randomized trial.” Obstet Gynecol. 2006;107:247-255.42.  Kaszkin-Bettag M et al. “The special extract ERr 731 of the roots of Rheum rhaponticum decreases anxiety and improves health state and general well-being in perimenopausal women.” Menopause. 2007 Mar-Apr;14(2):270-83.43.  Heger M et al. “Efficacy and safety of a special extract of Rheum rhaponticum (ERr 731) in perimenopausal women with climacteric complaints: a 12-week randomized, double-blind, placebo-controlled trial.” Menopause. 2006 Aug 4.44.  Rotem C et al. “Phytocomplex for the relief of hot flushes, night sweat and quality of sleep: Randomized, controlled, double-blind pilot study. Gynecol Endocrin. 2007;23(2):117-122.45.  ibed.46.  Meissner HO et al. “Hormone-balancing effect of pre-gelatinzined organic maca:III) clinical responses of early-postmenopausal women to maca in double blind, randomized, placebo-controlled, crossover configuration, outpatient study. Int J Biomed Sci. 2006;2(4):375-394.47.  Kwee SH et al. “The effect of Chinese herbal medicines (CHM) on menopausal symptoms compared to hormone replacement therapy (HRT) and placebo.” Maturitas. 2007;58(1):83-90.48.  Chen LC et al. “A pilot study comparing the clinical effects of Jia-Wey Shiau-Yau San, a traditional Chinese herbal prescription, and a continuous combined hormone replacement therapy in postmenopausal women with climacteric symptoms.” Maturitas. 2003;44:55-62.49.  Woo J, Lau E, HoSC, et al. “Comparison of Pueraria lobata with hormone replacement therapy in treating the adverse health consequences of menopause.” Menopause. 2003;10:352-361.  50.  Rad M et al. “Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women.” Br J Clin Pharmacol. 2006 Sep;62(3):288-96.51.  Yang, HG et al. “A randomized, double-blind, placebo-controlled trial on the effect of Pycnogenol® on the climacteric syndrome in peri-menopausal women.” Acta Obstericia et Gynecologica. 2007;86:978-985.52.  Ziaei S et al. “The effect of vitamin E on hot flashes in menopausal women.” Gynecol Obstet Invest. 2007;64(4):204-7.53.  Barton DL et al. “Prospective evaluation of vitamin E for hot flashed in breast cancer survivors.” J Clin Oncol. 1998 Feb;16(2):495-500