Nonhormonal Management of Menopause-associated Vasomotor Symptoms: 2015 Position Statement of The North American Menopause Society

The North American Menopause Society (NAMS). 2015;22(11):1155-1174. 

In This Article

Nonprescription Therapies

Lifestyle Changes

Cooling techniques. Because hot flashes can be triggered by small core body elevations,[12,13,14] it is rational to propose lifestyle practices that lower core body temperature or that prevent it from rising to decrease VMS frequency. These include clothing adjustments (such as dressing in layers; wearing sleeveless blouses, natural fiber clothing that breathes, and light cotton night clothes; and avoiding pullover sweaters/tops and scarves) and environmental controls (keeping a hand fan, electric fan, or ice water nearby; putting a cold pack under the pillow and turning the pillow when feeling warm; using dual control electric blankets or a bed fan—a simple device that blows air under the top sheet; and lowering the room temperature). However, no clinical trial evidence supports the efficacy of cooling interventions as treatments for VMS. Level V evidence

Avoiding triggers. It is also often recommended that women avoid ‘‘triggers’’ such as alcohol, spicy foods, and hot foods or liquids. No clinical trials have studied the effect of presumed triggers, and the Melbourne Women’s Midlife Health Project found no significant association between alcohol intake and VMS.[15] Level V evidence

Exercise. The hypothesis that regular aerobic exercise might be associated with a reduction in VMS arose from observational studies that found that women who exercise regularly report having fewer VMS.[16,17,18] However, others have found no relationship between level of physical activity or exercise and VMS,[19] and exercise may trigger VMS in symptomatic women.[13]

The numerous RCTs of the effects of exercise on VMS have been summarized in several Cochrane reviews. 20-22 The first review [20] included one study, [23] the second review [21] included five studies, [24,25,26,27,28] and the third review [22] added two studies. [29,30]

Across all three Cochrane reports, the authors concluded that the evidence was insufficient to determine whether exercise is an effective treatment for menopausal symptoms, and the overall evidence was viewed as poor. Methods and exercise interventions varied widely across studies, for example: structured supervised walking versus yoga versus no intervention[26]; supervised prescribed aerobic exercise versus yoga versus usual activity plus omega-3 or placebo pills in a 1:1 ratio with each group[30]; thrice weekly supervised aerobic exercise class versus hormone therapy[23]and unsupervised aerobic training four times weekly versus controls plus lectures once or twice per month on physical activity and general health in both groups.[29] When three studies that compared exercise to no exercise were pooled, exercise had no effect on VMS frequency.[22] No difference was found between yoga and exercise in the two studies that made this comparison. In the study comparing exercise and HT, HT was far more effective than exercise in reducing VMS.

In a randomized trial published subsequent to the Cochrane reviews, 261 women were randomized to: 1) one-on-one consultation with a physical activity facilitator; 2) the same counseling plus a digital video disc, a booklet, and five study leaflets; or 3) a control group.[31] Women were followed for 6 months. The exercise goal was 30 minutes of moderate intensity exercise 3 to 5 days per week. Neither intervention had an effect on total VMS frequency or night sweats that was greater than control.

Although there are many health benefits for recommending that midlife women exercise, randomized trials to date do not support any benefit of physical activity for VMS. Level I evidence

Yoga. Randomized trials to date do not support the case that regular yoga practice will reduce VMS.[32,33] A systematic review and meta-analysis of five RCTs[25,26,34,35,36] found no evidence that yoga was an effective intervention for VMS or menopausal symptoms.[32] Yoga varied from Iyengar yoga, to traditional Indian yoga, an ‘‘integrated’’ approach to yoga, and a combination of Yogasana and Tibetan yoga; some included only poses, whereas others included poses, breathing, and meditation. Doses varied from 1 to 2 hours per session, 1 to 5 sessions per week, and 8 to 12 weeks. Comparison groups included no treatment, exercise, or both.

Two trials[37,38] published after the systematic review also found no effect of yoga on VMS. Newton and colleagues[37] conducted an RCT in perimenopausal and postmenopausal women with at least two VMS per day randomized to yoga (n=107), exercise (n=106), or usual activity (n=142). The yoga intervention used 12 weekly 90-minute yoga classes with daily home practice. There was no significant difference between groups in change in VMS frequency from baseline to 6 and to 12 weeks. Avis and colleagues[38] randomized 54 late perimenopausal and postmenopausal women aged 45 to 58 years with at least four VMS per day to one of three groups: yoga (n=18), health and wellness education (n=19, attention control group), or a wait-list control group (n=19). Yoga and education consisted of weekly 90-minute classes for 10 weeks, and yoga included recommended home practice. VMS frequency declined similarly in all groups. At 10 weeks, the mean decrease in VMS per group was 6.5 (66%) in the yoga group, 5.9 (63%) in the health and wellness group, and 4.2 (36%) in the wait-list control group. Level I evidence

Weight loss. One RCT suggests weight loss may alleviate VMS. Forty overweight or obese women with at least four VMS per day were randomized to a 6-month behavioral weight loss intervention or wait-list control.[39] Women randomized to the weight loss intervention lost significantly more weight (–8.86 kg) than women randomized to control (+0.23 kg; P < 0.0001) and had a significantly greater reduction in questionnaire-reported hot flashes (–63.0 over 2 wk) than women in the control group (–28.0; P=0.03). Reductions in weight and hot flashes were highly correlated (r=0.47, P=0.006). Changes in hot flash severity, bother, the number of physiologically measured hot flashes, and diary-reported hot flashes did not differ between groups.

Additional evidence comes from three studies in which weight loss was studied, but hot flashes were not a primary outcome. The first was a 6-month study of weight loss for urinary incontinence that included 154 women who reported hot flash bother (7.5-kg weight loss in intervention vs 2.0-kg loss in control).[40] The intervention was associated with significantly greater improvement in bothersome hot flashes versus control. Reductions in weight, body mass index, and abdominal circumference were related to significant decreases in hot-flash bother. The second analysis used data from the Women’s Health Initiative Dietary Modification trial (n=17,473).[41] Baseline presence and severity of hot flashes were identified via questionnaire: 65% of respondents reported no; 25% mild; 8% moderate; and 2% severe VMS. Compared with control, women randomized to the intensive intervention to promote healthy eating were more likely to lose weight and have VMS symptoms eliminated at 1 year (odds ratio, 1.14; 95% confidence interval, 1.01-1.28). Compared with women who maintained their weight, women who lost 10 lb or more were 23% more likely to eliminate VMS at 1 year, and those who lost 10% or more of their baseline body weight were 56% more likely to have this outcome. The third study was the Women’s Healthy Eating and Living study, a dietary intervention trial for women with breast cancer.[42] In a secondary analysis, women were classified as having no/mild symptoms versus moderate/severe symptoms (36% at study entry). At 2 years, women who had gained at least 10% of their prediagnosis weight had a 33% (P=0.003) greater risk of reporting moderate/severe VMS than those with stable weight; whereas those who lost at least 10% of their prediagnosis weight had a 28% (P=0.118) lower risk of reporting moderate to severe VMS. Taken together, these studies suggest that weight loss might be associated with a decrease in or the elimination of VMS. Level II evidence

Mind-body Techniques

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) was effective in reducing VMS problem ratings, but not VMS frequency, in two randomized, double-blind, controlled trials. MENOS 1 showed efficacy of group CBT compared with usual care in 96 breast cancer survivors,[43] and MENOS 2 showed efficacy of self-guided and group CBT compared with usual care in 140 perimenopausal and postmenopausal women without a history of breast cancer.A clinical psychologist administered the group CBT intervention, which involved psycho-education, paced breathing, and cognitive and behavioral strategies to manage VMS. Women were trained in relaxation and paced breathing. Discussion topics included the physiology of VMS, stress as a VMS trigger, negative beliefs about VMS, and sleep hygiene. The usual-care group received information about VMS, advice on treatment options and symptom management, and instructions for paced breathing and relaxation. In both studies, improvements were maintained at 26 weeks, and more women in the CBT group (65% to 78% across studies) reached a clinically significant threshold for improvement in VMS problem ratings than in the usual-care group. The self-guided CBT was identical to group CBT and included a self-help book completed during a 4-week period, two contacts with a clinical psychologist, weekly homework, and a CD for daily practice of relaxation and paced breathing. A follow-up study[45] revealed that beliefs about coping and control over VMS and belief about sleep and night sweats mediated the effect of CBT on VMS problem ratings. Both the group CBT manual [46] and the self-guided CBT manual[47] are available. CBT is an effective treatment for bothersome VMS for both breast cancer survivors and menopausal women. Level I evidence

Mindfulness-based stress reduction. Current evidence is limited for mindfulness-based stress reduction (MBSR) and hot flashes. MBSR emphasizes acceptance, mindfulness meditation, and yoga as coping mechanisms to handle stress.[48] Participants are taught to approach thoughts, feelings, and sensations in a nonreactive manner. An RCT of MBSR versus wait-list control was conducted with 110 women who had five or more moderate to severe hot flashes per day. The MBSR intervention was a standardized, widely used, 8-week program involving weekly 2.5-hour group classes, at-home practice (45 min x 6 d/wk), and an 8-hour in-person group retreat. After 20 weeks, the MBSR group showed greater reductions in hot flash intensity (21.62% vs 10.50%) and bother (44.56% vs 26.97%) than wait-list controls, but these differences were not statistically significant. Level II evidence

Paced respiration. Paced respiration is unlikely to provide any benefit for hot flashes. Paced respiration involves taking six to eight slow deep breaths per minute while inhaling through the nose and exhaling through the mouth. Paced respiration was shown to reduce hot flashes in small, laboratory-based studies,[49,50,51] but two larger studies did not show it to be more effective than other forms of breathing. In a randomized trial of 208 women, paced respiration was no better than shallow breathing or usual care for reducing hot flash frequency, severity, bother, or interference.[52] Similarly, in a randomized trial of 92 women, paced breathing practiced once or twice per day was no better than usual breathing for reducing hot flash scores (frequency x severity).[53] Level I evidence

Relaxation. Current evidence is limited and inconsistent on relaxation for hot flashes. A 2014 Cochrane review[54] and a 2008 systematic review[55] both concluded that evidence from RCTs of relaxation was insufficient. Not included in either review was a nonblinded randomized trial showing a reduction in hot flash frequency with applied relaxation (n=33) compared with a wait-list control group (n=27).[56] In all studies, results were inconsistent and quality was poor, primarily because of small sample sizes and lack of an appropriate attention control group.[49,50,56,57,58,59,60] Level II evidence

Clinical hypnosis. Current evidence for clinical hypnosis is limited but suggests it may be a promising strategy for managing hot flashes. Clinical hypnosis is a mind-body therapy that involves a deeply relaxed state and individualized mental imagery and suggestion. It has been widely used to manage other chronic symptoms, such as pain and anxiety. Hypnosis has been studied for the treatment of hot flashes in two trials— one randomized trial in breast cancer survivors[61] and one RCT in women with at least seven hot flashes per day.[62] In both trials, clinical hypnosis involved 5 weekly in-person sessions of hypnotherapy with at-home self-hypnosis practice. In the study of 60 women with a history of breast cancer, clinical hypnosis was significantly better at reducing hot flashes and improving mood and sleep than no treatment.[61] The more recent trial, the randomized, single-blind, controlled clinical trial of 187 postmenopausal women reporting at least 50 hot flashes a week at baseline, evaluated clinical hypnosis over 12 weeks against an active structured attention control.[62] Participants in the clinical hypnosis arm reported significantly lower hot flash frequency (74% vs 17%) and hot flash scores (frequency x severity, 80% vs 15%) than controls. In addition, physiologically monitored hot flashes were reduced significantly more in the hypnosis group than in the attention control group (57% vs 10%). Level I evidence

Dietary Management and Supplements

Soy foods and soy extracts. Soy is the most widely used isoflavone-containing food. Isoflavones are a class of phytochemicals, a broad group of nonsteroidal compounds of diverse structure that bind to estrogen receptors (ERs) in animals and human beings. Isoflavones have greater affinity for ER-β than for ER-α and possess both estrogen-agonist and estrogen-antagonist properties. The isoflavones include the biochemicals genistein, daidzein, glycitein, biochanin A, and formononetin. Genistein and daidzein are found in high amounts in soybeans and soy products as well as in red clover, kudzu, and groundnut ( Table1 ). The relative amounts of isoflavones vary, depending on the portion of the soybean from which the material is obtained. The whole soybean contains about equal amounts of genistein and daidzein, with smaller amounts of glycitein. Some soy supplements are made from soy germ, which is higher in daidzein than genistein. Therapeutic efficacy of soy supplementation may vary based on the relative amounts of genistein and daidzein. Individual isoflavones, such as genistein, may have different therapeutic outcomes when administered alone than when the same amounts are administered with all three isoflavones (genistein, daidzein, and glycitein) in the supplement.

Although soy protein is low in potential adverse effects, prevalence data for soy protein intolerance are scarce. Common symptoms of use include bloating, flatulence, and loose stools. Soy protein is on the list of primary allergens in the United States and Canada.

About 30% of North American women have the ability to metabolize daidzein to equol. Equol is a nonsteroidal estrogen that binds to both estrogen receptors but with a high affinity for ER-β thus, it is often designated as an ER-β agonist. Equol is produced from daidzein by intestinal bacteria and is thought to be a stable characteristic that is best revealed after a soy challenge of just a few days. Equol has two isomers, S(-)- equol and R(+)-equol. Only S(-)-equol is detected in the plasma of equol-producing women and thought to have any biologic activity. By far the most exciting research opportunities in the area of soy isoflavone menopausal health concern the potential benefits of equol and the unanswered issue of whether equol is merely a marker for some beneficial effect of gut bacteria on steroid metabolism. More research is needed that compares equol producers with equol nonproducers.

Efficacy. The literature on soy foods and extracts, including derivatives and metabolites, has been the subject of intense scrutiny through meta-analyses (eg, Chen and coleagues[63]); systematic reviews (eg, Utian and colleagues[64]; Kronenberg and Fugh-Berman[65]); a NAMS Translational Science Symposium and publication[66]; and a Cochrane Collaboration analysis[67]—all within the last 2 to 4 years.

The most recent randomized, blinded, comparative clinical trials on soy isoflavonoids reviewed in the analyses have found them to be no more effective than a placebo. Most studies have been criticized for numerous study design defects. Other limitations are that manufacturing processes are multiple and largely uncontrolled, with resulting composition and batch-to-batch variation that may differ significantly, and that any benefits associated with isoflavones may occur more slowly and to a lesser extent than those achieved with traditional medications. In addition, there may be a difference between women who can convert the isoflavone daidzein to equol—and hence show efficacy of a supplement— and nonconverters, who would be unlikely to respond. A deficiency in most studies has been the fact that the study population has not been so defined. A supplement containing natural S-equol has been developed for women who do not have the capacity to produce equol,[64,66,67] but additional research is needed to determine whether the supplement may be effective for these women. Level II evidence

Over-the-counter supplements and herbal therapies.
Black cohosh. Black cohosh, scientific name Actaea racemosaL (previously Cimicifugae racemosae), has been used by Native Americans as a medicinal plant but was not used in traditional folk medicine as a menopause remedy. Nonetheless, it is the most commonly purchased botanical for menopausal symptoms. The active ingredients in black cohosh extract are unknown, and mechanism of action is unclear. At one time it was thought to be estrogenic, with in vitro and in vivo assays indicating estrogen-like activity.[68] More recent studies indicate activity similar to selective ER modulators[69] or modulation of serotonergic pathways, as well as antioxidant and anti-inflammatory effects.

A 2012 Cochrane review[70] analyzed 16 RCTs of 2,027 perimenopausal or postmenopausal women treated with black cohosh using a median daily dose of 40mg for a mean duration of 23 weeks. There was no significant difference between black cohosh and placebo in the frequency of hot flashes. Data on safety were also inconclusive. The authors concluded that, at this time, there is insufficient evidence to support the use of black cohosh for menopausal symptoms. Level I evidence

Black cohosh appears to have no effect on circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, or estradiol. A 52-week study reassuringly demonstrated that black cohosh does not increase endometrial thickness on ultrasound.[71] Reports of possible hepatotoxicity started to appear after 2000. After examining all reported cases, the US Pharmacopeial Convention’s Dietary Supplements-Botanicals Expert Committee found only 30 reports possibly related to black cohosh. The committee issued a directive that black cohosh products carry a warning statement: ‘‘Discontinue use and consult a healthcare practitioner if you have a liver disorder or develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice.’’[72]

Crinum. Crinums (genus Crinum) are members of the amaryllis family (Amaryllidaceae) and are widely used in folk medicine in South Asia. Extracts are said to exert antitumor, immune-modulating, analgesic, and antimicrobial effects.[73] The branded product, Crila, is sold for VMS. No studies of Crila can be found in the available medical research literature. Level V evidence

Dioscorea (wild yam). Dioscorea barbasco, D mexicana,, and D villosa are the varieties most commonly used. D villosa, also known as Mexican yam or wild yam root, contains diosgenin, a steroid precursor used in the manufacture of synthetic steroids. Diosgenin is converted in vitro to progesterone, but there is no biochemical pathway for this conversion in vivo. Alternative medicine practitioners suggest that yams have dehydroepiandrosterone-like activity and serve as precursors for the endogenous production of sex hormones, including estrogen and progesterone. When D alata was substituted for other carbohydrates twice daily for 30 days in the diets of 24 Japanese women, they showed significant increases in serumconcentrations of estrone (26%) and sex hormone-binding globulin (9.5%) and a near-significant increase in estradiol (27%), unlike 19 women fed plain sweet potatoes.[74] The pathway for these hormonal effects may reside in metabolic alterations other than steroidal conversion, perhaps modification of the enterohepatic circulation.

Evidence for efficacy of Dioscorea on VMS is limited. One clinical trial employing a yam cream to treat menopausal symptoms reported no significant benefit.[75] Yam creams that have been tested often do not contain any yam extract, and many have been adulterated with undisclosed steroids, including estrogens, progesterone, and medroxyprogesterone acetate (MPA). Because of the potential harm that might result from adulterants and lack of efficacy data, yam creams are not recommended for VMS. Level II evidence

Dong quai. Dong quai, also known as Angelica sinensis, dang gui, and tang kuei, is the root of the Angelica polymorpha Maxim var sinesis Oliv. It has been used as a female balancing agent in traditional Chinese medicine and as a panacea for gynecologic complaints. Dong quai is reputed to be estrogenic, based on reports of uterine bleeding with use and uterotropic effects in ovariectomized rats.[76]Human studies, however, have not found any evidence of estrogenic activity.

Dong quai does not appear to be effective for VMS, and there are a number of safety concerns, including possible photosensitization, anticoagulation, and possible carcinogenicity. Hirata and colleagues,[77] enrolled 71 women in an RCT of 4.5 g dong quai per day or placebo. After 24 weeks, there were no differences in the VMS frequency; Kupperman Index scores; levels of FSH, LH, and estradiol; vaginal maturation index; or endometrial thickness. Critics have stated that the dose was much lower than in traditional Chinese medicine formulations and that dong quai is not used alone but rather must be given in concert with other botanicals to promote the synergies needed for therapeutic effect. (See the information on combination botanical products.) Level II evidence

Evening primrose. Evening primrose, Oenothera biennis L, is a flowering plant rich in linolenic acid and γ-linolenic acid. Evening primrose oil (EPO) is recommended for a wide array of inflammatory and autoimmune disorders including allergies, eczema, arthritis, diabetic neuropathy, mastalgia/mastodynia, and inflammatory or irritable bowel disease. There is a single trial of EPO for menopause in which 56 women were randomized to EPO 500 mg per day or placebo for 6 months. Only 18 women taking EPO and 17 taking placebo completed the trial. EPO proved ineffective, with hot flashes declining by 1.0 per day with EPO and by 2.6 per day with placebo.[78] Level II evidence

Flaxseed. Flaxseed or linseed (Linum usitatissimum) is a rich source of lignans, polyphenolic sterols that, when acted on by microbiota in the gut, produce enterodiol and enterolactone, both weakly estrogenic sterols. The lignans in flaxseed reside in cell walls and are not bioavailable without extensive crushing. Highly milled flax flour and flax meal, but not flaxseeds, are sources of lignans in the human diet. Flaxseed oil, a good source of polyunsaturated fatty acids such as α-linolenic acid, provides no lignans. Flaxseed meal, flour, and oil are safe as foods.

To date, the accumulated evidence for flaxseed does not support its use for VMS. Dew and Williamson[79] reviewed flaxseed as a menopausal remedy and found a total of five relevant studies consisting of (at least) 437 flax and placebo volunteers, but none reported a benefit for VMS frequency/ severity beyond placebo. Within their review, they mentioned Pruthi and colleagues,[80] who enrolled 188 women in a randomized trial using a flaxseed nutritional bar with 410 mg of lignans or a placebo bar for 6 weeks. Although the mean hot flash severity score change was not significant, 4.9 in the flaxseed group and 3.5 in the placebo group (P=0.29), the authors noted a significant improvement in VMS interference with leisure activities. LeMay[81] reported flax as an effective remedy because it appeared to have comparable efficacy to 0.625 mg conjugated equine estrogens (CEE) as a positive control. Kupperman Index scores decreased from baseline by 24.2% (P < 0.001) and 32.7% (P < 0.01) for flax and HT, respectively. No placebo arm was included in the study. Level I evidence

Ginseng. There are two distinct true ginsengs in common use, Panax ginseng, also known as Asian, Korean, or Chinese red ginseng, and American ginseng (Panax quinquefolius), sometimes called white ginseng. A third substance, Siberian ginseng (Acanthopanax senticosus or Eleutherococcus senticosis), is not a true ginseng but a member of a closely related family of plants, Araliacea, which also includes sarsaparilla. Some safety issues have been raised, particularly when ginseng is used in energy drinks with other stimulants.

Ginseng does not appear to be effective for VMS. In a study of a specific proprietary product, G115, sold in the United States as Ginsana,[82] 384 postmenopausal women were randomized to G115 or placebo. After 16 weeks, women taking G115 showed slightly better overall symptom relief, but changes were not statistically significant (P < 0.1) and accrued only from improvements in depression, well-being, and health scores, not VMS. Ginseng had no effect on FSH, estradiol, endometrial thickness, vaginal maturation index, and vaginal pH. Kim and colleagues measured hot flash frequency with Korean red ginseng versus placebo and found no statistically significant difference between groups.[83] A second study from the same team[84] found that ginseng improved both Kupperman Index (P=0.032) and Menopause Rating Scale scores (P=0.035) but failed to specifically affect hot flash scores within either scale (P=0.046 and P=0.121, respectively). These findings were later summarized in a review by Kim and colleagues.[85] Level I evidence

Hops. The female flowers of hops (Humulus lupulus), also called the seed cones or strobiles, are used in beer, often to add a bitter, tart flavor to other grains. The plant makes a flavonoid, 8-prenylnaringenin, which is said to have greater estrogenic activity than soy-derived isoflavones.

Evidence for hops is limited and inconsistent. There are two trials using hops to treat symptoms of menopause. The first included 67 women randomized to two standardized doses of hops extract (100µg or 250µg) or placebo.[86]Hops 100 mg was better than placebo at 6 weeks (P=0.023) but not at 12 weeks (P=0.086). The 250-µg dose offered no therapeutic efficacy over placebo. In the second study,[87] 36 women were randomized to either hops or placebo for 8 weeks and then crossed over for 8 additional weeks of the alternate treatment. Outcome measures included scores on the Kupperman Index, the Menopause Rating Scale, and a multifactorial visual analog scale at baseline, 8, and 16 weeks. The researchers reported no significant reduction (P=0.06) on the Menopause Rating Scale after 16 weeks. Level II evidence

Maca. Maca (Lepidium Meyennii Walp, Lepidium peruvianum Chacon), a traditional foodstuff from South America, is a cruciferous root grown exclusively in the central Peruvian Andes at 12,000 to 14,000 feet altitude. It is recommended as a tonic and adaptogen, characterized as ‘‘Peruvian ginseng,’’ and used for strength and stamina, athletic performance, anemia, and fertility and as an aphrodisiac.

The mechanism of action of maca on male and female hormones remains to be elucidated but is postulated to be modulation of sex steroid-receptor dynamics. Maca contains a weak phytosterol, β-sitosterol, also found in several other botanicals, such as saw palmetto, which is often recommended as a treatment for prostate problems. Both methanolic and aqueous extracts of maca exhibit estrogenic activity in vitro, but studies have found no in vivo estrogenic effects.

In a systematic review, only four maca studies were evaluable. All showed improvements in Greene Climacteric Scale or Kupperman Index scores, but all were poor quality with poor trial design, very small sample sizes, or limited reporting of study data.[88] Thus, these studies are not strong enough to support the use of maca for VMS. Level II evidence

Omega-3 fatty acids. Omega-3 supplements contain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-linolenic acid. Phospholipids, a major component of neuronal cells, contain a high prevalence of fatty acids. Two trials have evaluated omega-3s for VMS. In an 8-week trial of 91 women randomized to placebo or omega-3 supplement (total daily dose: EPA 1,100 mg + DHA 150 mg), VMS frequency and intensity were significantly improved with omega-3 compared with placebo.[89] In a 12-week trial, women were randomized in a 1:1 ratio to omega-3s (n=177) or placebo (n=178) and simultaneously in a 3:3:4 ratio to yoga (n=107), aerobic exercise (n=106), or their usual physical activity (n=142). There were no significant differences in VMS frequency or bother with omega-3s or placebo. The total daily dose of omega-3 was EPA, 1,275 mg; DHA, 300 mg; and other assorted omega-3s, 270 mg.[90] Level II evidence

Pine bark. Pine bark from the Mediterranean pine (Pinus pinaster) serves as a source of proanthocyanidins, the same group of compounds found in grape seeds. Proanthocyanidins derived from pine bark are promoted as antioxidants and are sold under the registered trademark name Pycnogenol.

Three trials evaluated Pycnogenol for menopausal symptoms, but none included detailed measures of VMS. The first randomized 200 women to 200 mg or placebo,[91] with 175 completers and 155 providing complete data. Using the Women’s Health Questionnaire, the researchers reported significant improvements in all scale domains, including one pertaining to VMS symptoms. In another trial, 38 women given 100 mg Pycnogenol daily for 8 weeks showed greater improvement in VMS compared with a parallel (nonrandomized) group of 32 untreated women.[92] Third, 170 perimenopausal women were randomized to 30 mg Pycnogenol twice daily or placebo with 156 women—78 women in each arm— completing the study.[93] After 12 weeks, symptoms were significantly more improved with treatment than placebo, based on Women’s Health Questionnaire vasomotor scores (P <0.05) and total Kupperman Index scores (P < 0.05). These studies suggest Pycnogenol might offer some benefits in relieving symptoms, but data to date are not of sufficient quality to document the degree of therapeutic benefit, and the effective dose has yet to be determined. Pycnogenol is possibly safe, but the safety of other pine bark preparations cannot be assured. Level II evidence

Pollen extract. A proprietary extract made from flower pollen, Relizen, has been recently introduced in the United States. This product has been available in the European Union (EU) since 1999 and sold under the brand names Serelys, Femal, and Femalen. Its constituents are pollen cytoplasmic extract (GC Fem) and pistil extract (PI 82), and the proposed mechanism of action is said to be antioxidant and antiinflammatory. The current product contains 40 mg of GC Fem and 120 mg of PI 82. Older formulations sold in the EU also contained vitamin E. The manufacturer states that there is no pollen in the product and that it is safe for persons with pollen allergies. In vitro and animal studies found pollen extract does not specifically bind to estrogen receptors and has no estrogenic activity[94] (Prof. Dr. Eduardo Munõz, Department of Cell Biology, Physiology and Immunology, University of Córdoba, VivaCell Biotechnology GmbH. Unpublished data, 2012).

There is only one small RCT of pollen extracts in menopause.[95] Sixty-four postmenopausal women were randomized, with data reported for 53 completers. After 3 months and compared with placebo, significant reductions in VMS were seen on the Menopause Rating Scale (65% vs 38% reporting reductions) and daily diaries (27% greater reduction with treatment). The Menopause Rating Scale evidenced significant improvements in other quality-of-life parameters in the pollen extract group (P < 0.031). More studies are needed. Level II evidence

Puerpuria. Pueraria mirifica, also known as kwao krua, is a plant found in northern and northeastern Thailand and Myanmar. The plant is estimated to contain 8% to 10% isoflavone by dry weight.

Two small studies reported the effects of puerpuria on menopausal symptoms, but neither included specific measures of VMS. In one study, 52 hysterectomized, symptomatic women were randomized to P mirifica 25 mg or 50 mg per day and followed for 6 months. No placebo was included. On the Greene Climacteric Scale, the baseline scores were 24.19±9.11 and 23.19±7.89, respectively. After 3 months of treatment, scores were 17.92±10.40 for the low dose and 15.35±8.44 (P=0.332) for the high dose. After 6 months, the scores were 14.08±10.30 for the low dose and 12.46±6.38 (P=0.500) for the high dose.96 No significant adverse effects were seen at either dose. In a second study, 71 women were randomized to 50 mg raw P mirifica or 0.625 mg CEE, with or without 2.5 mg MPA, depending on whether they had an intact uterus.[97] Data from 60 completers were reported but lacked detail. The researchers claimed that both treatments performed equally well and that measures of estradiol, FSH, and LH were also similar in both the P mirifica and CEE groups. The lack of a placebo arm and poor reporting of data in both studies are limitations. Level II evidence

Siberian rhubarb. Siberian rhubarb (Rheum rhaponticum) is used as a food and as a medicinal plant for constipation, diarrhea, and other gastrointestinal complaints. It has laxative qualities that are similar to extracts from senna plants. Two hydrostilbenes found in rhubarb, rhapontigenin and desoxyrhapontigenin, have very weak binding affinity for ER-α, with higher affinity for ER-β. In vitro and in vivo studies support the hypothesis that the hydrostilbenes in rhubarb act as selective estrogen receptor modulators (SERMs) with mixed agonist/antagonist activity.[98]

A single commercial preparation of rhubarb extract, which has been used Germany for more than 20 years, was introduced in the United States and sold as Estrovera. The product contains a proprietary extract called ‘‘rhaponticin’’ or ‘‘extract ERr 731.’’

One study evaluated this product for menopausal symptoms but did not include detailed measures of VMS. Heger and colleagues[99] randomized 109 symptomatic perimenopausal women to one enteric-coated tablet of ERr 731 (n=54) or placebo (n=55) daily for 12 weeks. Only 7 of 55 women randomized to placebo (12.7% retention rate) and 39 of 54 women randomized to active treatment completed the trial. Given the small number of completers, the study is probably underpowered. Nonetheless, the researchers reported that at 12 weeks, the Menopause Rating Scale II total score, and each symptom within the scale, significantly improved in the active-treatment group versus placebo (P <.0001).

The manufacturer has long-term safety data collected from beagle dogs and states that no abnormal hematologic or metabolic trends have been seen, even at high doses.[100] Human safety data were drawn from a group of 23 women followed up for 48 weeks, 20 of whom completed a 96-week observation period. Few adverse events were reported.[101] Additional evidence is needed on both efficacy and safety for use in VMS. Level II evidence

Combination botanical remedies. Combination botanicals are frequently used by herbal medicine practitioners, most often some variation on a multiple botanical formulation recommended in traditional Chinese medicine. Combinations are said to offer better outcomes because of the complexity and variety of menopause-related symptoms. Whether this is sound or logical is open to question because one agent, estrogen, effectively mitigates most, if not all, menopausal symptoms.

Botanical combinations, although proffering better symptom relief, are difficult to assess, given the complexity of the formulations, the potential for adverse events, and the difficulty in predicting drug-herb interactions ( Table 2 ).[102,103,104,105,106,107,108,109,110,111,112,113,114] (Mary Tagliaferri, MD, Founder, Dr. Tagliaferri Formulas, email communication, 2015) The botanical combinations listed in  Table 2 have been tested in at least one published clinical trial. Most of the trials referenced suffer from the same types of methodological problems noted above for single-agent botanicals. Level II evidence

Vitamins. Three trials show varying evidence for vitamin E on VMS. In one crossover trial, 120 women were randomized to 4 weeks of vitamin E (800 IU) followed by placebo or vice versa.[115] Although there was a subjective decrease in VMS with vitamin E, the reduction was only by about one hot flash per day; the authors concluded this was not clinically meaningful. However, another crossover trial of 50 postmenopausal women comparing 4 weeks of vitamin E (400 IU) followed by placebo or vice versa found a greater reduction in hot flash frequency of about 2 hot flashes per day (P < 0.0001) and hot flash severity (P < 0.0001) with vitamin E.[116] In a third trial, 115 women were randomized to vitamin E or gabapentin with significantly greater reduction in VMS with gabapentin. Thirty-five percent of the vitamin E group dropped out because of lack of efficacy.[117] Level I evidence

Evidence for other vitamin supplements is mixed. A multivitamin and mineral supplement was studied in a double-blind, randomized, placebo-controlled trial of 99 women, 70 of whom completed the study. At 3 months, there was no significant difference in VMS between groups.[118] In another study of 46 women, vitamin B9 (folic acid) 5mg daily for 4 weeks was found to reduce VMS significantly more than placebo.[119] Further trials are needed to attempt to replicate these findings in larger, more diverse samples. Level II evidence

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