Botanical Medicines and Phytonutrients in the Management of Menopausal Hot Flashes

Abstract

Hot flashes and night sweats (vasomotor symptoms [VMS]) are exceedingly common during the menopausal transition, affecting up to 80% of women. A variety of botanical medicines and phytonutrients are popularly used to address VMS. These include soy isoflavones, black cohosh, flaxseed lignans, red clover extracts, and Siberian rhubarb. This article reviews the evidence for the use of these botanical medicines or phytonutrients in addressing menopausal hot flashes. Safety and adverse effects are also discussed. By and large, these botanical medicines have been found to be both safe and efficacious for menopausal VMS.

Background

Vasomotor symptoms (VMS) including hot flashes and night sweats are a common occurrence during both perimenopause and menopause. Close to 80% of perimenopausal women and 65% of postmenopausal women experience VMS.¹ VMS are also highly durable, lasting an average of 7–10 years for those with frequent or moderate to severe symptoms, and even longer for women with less frequent or milder symptoms.² Hot flashes can vary widely in severity, with some women experiencing mild VMS and others more substantial symptoms that may strongly impact quality of life (QOL).

While there is plenty of individual variability, hot flashes are generally experienced as episodes of transient, marked increases in sweating, or subjective sensations of heat, often with a surge in cutaneous vasodilation.^3,4 Hot flashes may also be accompanied by dizziness, tachycardia, a prickling sensation to the skin, anxiety, or nausea.^4,5 Some women may also experience a premonitory aura (described as queasiness, anxiety, a sensation of unease, or pressure in the head) prior to the onset of a hot flash. In one study, aura was experienced by women with hot flashes 38% of the time, with 55.2% of women reporting the occurrence of hot flash aura.⁵ Hot flashes may occur with or without particular triggers, with some women noting that intake of alcohol, caffeine, or spicy foods may trigger symptoms, that hot or humid conditions may be a trigger, or even strong emotions or high stress.⁶

The occurrence and severity of VMS may be higher in women with surgical menopause, as well as in cancer survivors.³ Studies also indicate a variety of other factors associated with increased hot flash severity, although the results specific to some factors are mixed. Women who smoke may experience more severe hot flashes, as may women who are African American.^7,8

In one study, severity of hot flashes was associated with older age, earlier age at onset of menopause, and higher anxiety, and hot flash severity peaked during late menopause and diminished after the second year postmenopause.⁹ In another, hot flash severity correlated with early postmenopausal status, while there was no association with psychosocial or lifestyle factors (including anxiety, stress, depression, activity levels, or body mass index [BMI]).¹⁰ This contrasts with other data showing that women with higher BMI may have more bothersome hot flashes.⁷ Lower estrogen levels and higher follicle stimulating hormone (FSH) are stable predictors of hot flash symptoms. But in spite of the fact that all women experience these hormonal changes during the menopausal transition, not all women experience hot flashes. This highlights the fact that other physiologic factors play an important role.

While the underlying physiology of VMS is not completely understood, heart rate (obtained from electrocardiogram) has been shown to increase significantly during hot flashes, and some women may experience drops in blood pressure (in one study, arterial blood pressure decreased by a mean of 13 ± 2 mm Hg in some women with hot flashes).³ Skin temperature may also increase related to vasodilation, with some studies showing increases in digit skin temperature of 1°C–7°C. Peripheral cortisol levels have also been shown to increase during a hot flash.⁶ Various models for VMS have been proposed (see Sidebar). This includes a narrowing of the thermoneutral zone, the body temperature range between upper (sweating) and lower (shivering) temperature thresholds.^2,11

Models or Mechanisms of VMS

Thermoregulatory model: Thermoregulatory function may be altered; women with hot flashes may have a narrower thermoneutral zone during menopause, so small changes outside this zone may trigger VMS.

Autonomic model: Alterations in autonomic nervous system function may occur, with higher sympathetic or lower parasympathetic control over heart rate during hot flashes demonstrated in a number of studies.

Central/hypothalamic mechanisms: Hypothalamic kisspeptin, neurokinin B, or dynorphin neurons potentially implicated in the generation of VMS.

If hot flashes are mild or infrequent, they may not be particularly bothersome. If symptoms are more significant or frequent, on the other hand, they may have a strong impact on QOL. VMS can impact sleep or mood function, and are associated with poor sleep, fatigue, depression, and anxiety.^5,6 Hot flashes may also be associated with poorer sexual function.⁵ Beyond concerns related to QOL, VMS in menopausal women may also serve as a marker of later cardiovascular risk and bone health. Initial observations related to VMS and the risk of cardiovascular disease (CVD) came from the Women's Health Initiative (WHI) and the Heart and Estrogen Replacement Study trials. With their data indicating that the relationship between menopausal hormone therapy (MHT) and risk of CVD was modifiable not only by age but also by the occurrence of VMS, these studies suggested there may be a different vascular phenotype for women who don't experience hot flashes, compared to women that do.²

In the Study of Women's Health Across the Nation (SWAN) Heart study, women with hot flashes (excluding those with baseline CVD) had higher levels of aortic calcification and poorer endothelial function than those without, even after adjusting for estradiol (E2) and FSH levels as well as CVD risk factors. Women with VMS also had higher carotid intima media thickness. These associations were strongest in participants who were either overweight or obese. For the purposes of this trial, hot flash severity was not examined, and women were simply classified as either having hot flashes, or not having hot flashes.²

In the Women's Ischemia Syndrome Evaluation (WISE) study, women with myocardial ischemia signs or symptoms who had a history of earlier onset hot flashes (< age 42) had poorer endothelial function and higher CVD mortality than women with later-onset VMS.¹² Younger women (ages 40–53) who experience hot flashes have also been shown to have reduced flow-mediated dilation compared to women without hot flashes. This association persists even after controlling for E2 levels, indicating an estrogen-independent mechanism.¹³ Findings such as these are important since endothelial dysfunction is predictive of future vascular events, and plays a crucial role in CVD progression.

Specific to bone health, VMS may also predict a women's bone mineral density (BMD). In an analysis from the bone substudy of SWAN, data from 2213 participants indicated that postmenopausal women with VMS had lower lumbar and total hip BMD than those without VMS (0.008 g/cm² lower for lumbar, P = 0.001 and 0.005 g/cm² lower for hip, P = 0.04). Likewise, early perimenopausal women with VMS and premenopausal women with VMS had lower femoral neck BMDs than their counterparts without VMS. This was after controlling for age, race/ethnicity, and baseline menopause stage. BMD was also consistently lower among those participants with frequent VMS (defined as occurring ≥6 days in the preceding 2 weeks) compared to participants without frequent VMS.¹⁴

This association was also seen in the Eindhoven Perimenopausal Osteoporosis Study. In a population-based sample of 5600 women, average BMD decreased with increasing occurrence of hot flashes and night sweats (P for trend <0.0001 and P for trend = 0.03 respectively). Women with the highest frequency of VMS had a 0.022 g/cm lower BMD compared to women without, after adjusting for age, BMI, menopausal status, smoking, education level, exercise, and hormone use.¹⁵ Additional data from the WHI (with 23,573 participants not on MHT) indicates that women with moderate or severe VMS have not only lower BMD but also increased rates of hip fracture (hazard ratio 1.78, 95% confidence interval [CI] 1.20–2.64; P = 0.01).¹⁶

It remains unknown if treating menopausal VMS will improve cardiovascular or bone outcomes, and studies examining these questions are still needed. In spite of this, addressing VMS can improve a woman's overall health status or QOL in many cases by leading to improved sleep or mood for example. For this reason, treating menopausal hot flashes can be highly beneficial in women with bothersome symptoms. The only nonhormonal treatments for VMS that are currently FDA-approved are paroxetine and fezolinetant. Clinical trials of paroxetine demonstrate reductions in hot flash frequency ranging from 30% to 65% with 6–12 weeks of treatment, and two phase 3 trials for fezolinetant demonstrated 51%–55% reductions in hot flashes with 4 weeks of treatment.^17
–19

In patients in whom these pharmaceutical options are not appropriate, there is a need for additional evidence-based therapies. This article reviews the use of botanical medicines or phytonutrients for menopausal hot flashes. Some of the botanical medicines reviewed in this article are considered phytoestrogens (nonsteroidal plant-derived compounds with structures similar to 17-β-estradiol). Phytoestrogens can be generally classified into one of three different categories²⁰:

Isoflavones: sourced from legumes, such as soy.

Lignans: sourced from seeds, fruits and vegetables, or grains.

Coumestans: sourced from legumes, clover, and alfalfa.

Flax Lignans

Flaxseed (Linum usitatissimum) is a rich source of lignan compounds, especially the lignan secoisolariciresinol diglucoside (SDG). After consumption, SDG is converted by gut flora to enterodiol and enterolactone lignans (with that conversion varying on the individual level). These compounds have been shown to have antioxidant and anti-inflammatory activities in addition to acting as phytoestrogens.²¹ These metabolites of SDG have also been demonstrated to have greater estrogen-modulating and antioxidant activity than the parent compound itself. While this certainly seems promising, clinical trials have failed to demonstrate major benefits for flax surpassing those of placebo, in the case of menopausal hot flashes.

In a six-month trial in 90 menopausal women (average age 55.2 years), the use of whole flax meal was compared to supplementation with flaxseed extract. One group took 1000 mg flaxseed extract (containing 100 mg standardized SDG total) in capsule form once daily. Another took 2 tablespoons of ground flaxseed once daily (containing 270 mg lignans as SDG). Yet another took 1000 mg collagen capsule daily as a control. At the conclusion of the trial, the decrease in hot flash scores (assessed by Kupperman Index) was not significantly different for flax group versus placebo (1.59 ± 2.84 points for the flax supplement group, 1.04 ± 1.99 points for the ground flax meal group, and 0.21 ± 1.49 points for placebo, P = 0.084). While these results did not reach statistical significance, the authors noted that there was tendency for the Kupperman index to decrease in both the flaxseed extract and the flaxseed meal groups.²²

In another small randomized clinical trial (RCT) in 38 postmenopausal women, consumption of a flax-enriched bread (25 g whole flax, containing a total of 46 mg SDG lignans) was compared to a wheat bran-enriched matched bread (<1 mg lignans) as a control. Patients consumed the respective intervention once daily for three months. At the conclusion of the trial, both groups had a significant reduction in hot flashes (P < 0.05, assessed by Kupperman Index), but results for flax were no different than those seen with the placebo. The authors noted that the placebo effect for interventions for hot flashes has been demonstrated in previous study to range from 20% to 30% reductions in number/severity of VMS over four-week treatment periods.²³

In another phase III, placebo-controlled RCT from the North Central Cancer Treatment Group, the use of a higher dose of lignans was examined in postmenopausal women either with or without breast cancer (N = 188). Participants were randomly assigned to either a flaxseed bar group (containing 410 mg of lignans) or a placebo bar group, once daily for six weeks. Subjects kept a hot flash diary throughout. Mean hot flashes were reduced in both groups, but the difference between the two was not significant (hot flash score decreased by 4.9 points in the flax group and 3.5 in the placebo group, P = 0.29). In each group, roughly one-third of participants reported a 50% reduction in their hot flash scores.²⁴

A systematic review performed by Dew and Williamson examined results from 11 controlled clinical trials with 632 participants, with respect to flax and menopausal hot flashes. Included studies ranged in length from 6 weeks to 12 months. Only four of the included trials specified the secoisolariciresinol or SDG content of the flax intervention, and an additional three trials specified total lignan content. Flaxseed amounts utilized in the included trials ranged from 7.5 to 45 g daily. Although several of the included trials reported significant reductions in either frequency or severity of hot flashes, reductions were not significantly different from that seen with controls. Of five studies that compared flax to placebo, none demonstrated a benefit for flax that was different from the effect seen with placebo.²⁵

Because the trials described above made no specific concessions for nor mention of the participants' microbiomes, it is unclear if that may have affected the results observed. Certainly, the intestinal flora of each individual is a strong determinant of the bioavailability and activity of these flax phytoestrogens.²⁶ In spite of the perhaps unexciting results seen in the trials mentioned above, flaxseed and its lignan compounds do appear to be safe for use by the majority of adults.²¹ Intake of flaxseed does not appear to alter circulating levels of sex hormones, although it has been shown to increase the urinary 2-hydroxyestrone/16α-hydroxyestrone ratio, a beneficial alteration which may be associated with a decreased risk of breast cancer.²⁵ Flaxmeal or flax extracts also do not affect endometrial thickness.²² Flax has even been demonstrated to not only be safe, but possibly beneficial, in women with hormone-receptor positive breast cancer.²⁷ Additionally, flax does not appear to interfere with the activity of aromatase inhibitors in women with breast cancer.²⁸

Even though the reduction in hot flashes seen with flaxseed consumption may not exceed that seen with placebo, it is a reduction nonetheless, and because flaxseed intake may offer other advantages (such as reductions in blood pressure in those who are hypertensive,²⁹ improvements in insulin sensitivity or lipid profile,³⁰ or improved fiber or omega-3 fatty acid intake), it may still be worth a trial in a woman experiencing bothersome VMS.

Soy Isoflavones

Soy foods are a rich source of isoflavones. Both soybeans and whole soy foods contain roughly 3.5 mg isoflavones per gram. This means that a standard serving of soy, such as 100 g of tofu, or 250 mL soy milk, would provide ∼25 mg isoflavone. Keep in mind this applies to whole/traditional soy foods, since more processed soy foods (e.g., soy protein concentrates or soy isolates) may lose up to 80% or 90% of their isoflavone content due to processing.³¹ While isoflavones are capable of binding to both estrogen receptor alpha (ERα) as well as ER beta (Erβ), they preferentially bind Erβ (in contrast to estrogen itself, which binds both receptors equally), and are therefore thought to act more as selective estrogen receptor modulators (SERMs). Due to differing receptor distribution in different tissue, isoflavones may therefore have estrogen-like effects in some tissues, while having neutral or antiestrogenic effects in others. This also means isoflavones may provide specific benefits, while avoiding the potential adverse effects of ERα activation.^20,31

Numerous studies have examined the question of soy isoflavones' effects on menopausal hot flashes. As a result, a number of systematic reviews and meta-analyses are also available. In Taku et al.'s 2012 meta-analysis, 17 trials were included, 13 of which assessed the effect of soybean isoflavones on hot flash frequency, and 9 of which assessed for the effects on hot flash severity. Supplementation with soy isoflavones (median, 54 mg aglycone equivalents) for periods of 6 weeks to 12 months significantly reduced the hot flash frequency by 20.6% compared to placebo (95% CI −28.38 to −12.86; P < 0.00001), and also reduced hot flash severity by 26.2% compared to placebo (95% CI −42.23 to −10.15, P = 0.001). Isoflavone supplements at doses >18.8 mg of genistein (the median for all included trials) were about twice as effective at reducing hot flash frequency than those with lower amounts.³²

One question of clinical importance is: when supplementing with soy isoflavones, how long it might it take for a woman to notice effects in terms of hot flashes? In a model-based meta-analysis, Li et al. pooled results from 16 placebo-controlled clinical trials of soy isoflavones, with a total of 1710 subjects, to try to answer this question. Both the doses of isoflavones utilized (ranging from 30 to 150 mg), and the duration of included trials (from 4 to 24 weeks), varied widely. Analysis revealed that the maximal percent reduction of hot flashes with soy isoflavones was 25.2%, after eliminating the placebo effect. Note that in this study, a duration of 13.4 weeks of use was required for soy isoflavones to reach half their maximal effect (noted to be much longer than that required with estradiol, at 3.1 weeks), and soy isoflavones required 48 weeks of use to exert 80% of their maximal effect on hot flashes. The authors therefore suggested that shorter trials, such as those lasting for 12 weeks, would not be sufficient to appreciate the complete benefits of soy isoflavones.³³

An additional model-based meta-analysis comparing soy isoflavones to other nonhormonal pharmacologic interventions for hot flashes has confirmed that soy isoflavones are effective, but take time to exert their benefits. Included in the analysis were 39 double-blind placebo-controlled RCTs. The median sample size for the included trials was 200, and the median duration for trials on soy isoflavones was 12 weeks, but ranged from 4 to 96 weeks.

After deducting the placebo effect, the maximal effect for SSRIs/SNRIs (selective serotonin reuptake inhibitors/serotonin norepinephrine reuptake inhibitors), gabapentin, clonidine, and soy isoflavones were as follows: 13.9%, 14.8%, 18.5%, and 25.0% (respectively). SSRIs/SNRIs, gabapentin, and clonidine provided more rapid relief of hot flashes, with the time required to achieve half the maximal effect being 0.18 weeks for SSRIs/SNRIs, 0 weeks for gabapentin, 0 weeks for clonidine, and 11.6 weeks for soy isoflavones. A duration of use of 16.6 weeks was required for the efficacy of soy isoflavones to surpass that of SSRIs.³⁴ Again, this points to the fact that it may take longer to see the clinical effects of soy isoflavones, that the effects of soy may be progressive over time, and that trials of shorter durations might not observe the maximal impact of these phytonutrients.

Aside from the duration of supplementation required to see effects, another important clinical question pertains to an individual's ability convert the isoflavone daidzein to equol. As with flaxseed lignans, this is an area where gut microflora play an important role, and a number of bacterial species in the gut are responsible for converting daidzein to equol. While these specific bacteria (such as Asaccharobacter celatus and Slackia isoflavoniconvertens) have been shown to be present in the gut flora of people who are equol-producers as well as those who are not, abundance and prevalence of these bacteria is significantly higher in equol producers. It has been theorized that daidzein intake itself from regular soy food consumption is responsible for increasing these bacterial species, so that higher intakes of soy may lead to a better ability to produce equol.³⁵

Equol and daidzein both appear to be well-absorbed, but equol is thought to be more bioactive than daidzein, possibly undergoing more rapid cellular uptake, and has been suggested to be a more potent phytoestrogen than precursor isoflavones. A few studies have pointed to equol production as a key moderator of the effects of soy on VMS. In one study of perimenopausal women, those who were equol producers (53.5% of subjects) had lower menopausal severity index scores. In another observational trial in perimenopausal and postmenopausal women who were frequent consumers of soy foods (≥3 servings/day), those who were equol producers had 76% less VMS than those who were not. Daily et al. have suggested that equol-producing status (or, supplementation with equol itself) may modulate the efficacy of soy supplementation (and may offer an explanation for why soy supplements benefit some, but not all, menopausal women with VMS.²⁰

In a systematic review and meta-analysis of RCTs, Daily et al. assessed the effects of equol supplementation, or of soy isoflavones in equol producers, for VMS in perimenopausal and menopausal women. Five studies (duration ranging from 8 to 24 weeks) were included in the meta-analysis, with a total of 728 participants. Equol was found to be safe, with no clear adverse effects demonstrated, and to perform significantly better than controls in reducing VMS (P = 0.004). As part of the review, the authors also determined that there seemed to be little benefit to supplementing women who are equol producers with additional equol or daidzein, as long as their diets were already rich in isoflavones.²⁰ The authors concluded that their study supported the use of equol supplementation at 10 mg per day in postmenopausal women with VMS who are not equol producing, or simply an isoflavone-rich diet in women who are already equol-producing²⁰ (although determination of equol producer status is not a commercially available form of testing, and is relegated to the realm of research, so it seems unclear from a clinical perspective how such would be determined).

A last question pertaining to soy supplementation is in regards to safety. Soy isoflavones have been consistently demonstrated to be safe. Soy has not been shown to have estrogenic effects in humans or to increase circulating estradiol levels.³⁶ Multiple trials demonstrate that soy isoflavone supplementation has no effect on endometrial thickness or endometrial hyperplasia.^37

–40 Additionally, isoflavone supplements and soy-rich diets do not increase mammographic breast density in postmenopausal women.^41

–44 Soy isoflavones have also been shown to be safe for both hepatic and thyroid function.^38,40

Patients may also enquire about soy isoflavones and breast cancer. Due to a lack of data, it has been the author's practice to avoid soy extracts or isoflavone supplements in women who are breast cancer survivors. However, these same women can be encouraged to include whole soy foods as part of the diet, a practice which has been demonstrated to not only be safe, but to perhaps be beneficial.^36,45 Women who include soy foods in the diet (at amounts that would be consistent with those seen in a traditional Japanese diet, such as 2–3 servings daily, providing 25–50 mg soy isoflavones) have been shown to have a reduced risk of breast cancer recurrence.³⁶

Siberian Rhubarb

Extracts of Siberian rhubarb, Rheum rhaponticum, have been the subject of a handful of clinical trials in women with VMS. These extracts are generally high in rhaponticin, a stilbenoid glucoside which appears to act as a SERM, working as a selective ERβ agonist in some tissue types, such as human endometrial cells, while having no significant effects on ERα.⁴⁶

In a 2006 multicenter, double-blind, placebo-controlled RCT by Heger et al., 109 perimenopausal women (age 45–55 with cycle irregularity during the preceding 12 months, or last menstrual period occurring 3–12 months prior) with VMS received either enteric-coated Siberian rhubarb extract 4 mg, or a placebo, once daily for 12 weeks. At the completion of the trial, Menopause Rating Scale II (MRS II) total scores as well as MRS II hot flash scores decreased significantly for women receiving the herbal intervention compared to placebo (P < 0.0001 for both). Additionally, women receiving Siberian rhubarb had significantly better menopause-specific QOL than did women in the placebo group (P < 0.05). There were no adverse events with the herbal intervention, and no differences in endometrial thickness, uterine bleeding, or laboratory safety parameters between the two groups.⁴⁷

The same group then performed a longer-term study with 48–96-week follow up in participants from the trial above. Following the above RCT, all participants were offered the option of taking Siberian rhubarb extract for 48 weeks. After that, participants could then elect to continue on the herbal intervention for an additional 48 weeks (96 weeks in total). Of the 109 subjects from the initial trial, 80 continued further, taking Siberian rhubarb for 48 weeks, and then 51 women also continued taking Siberian rhubarb up to the 96-week mark.

Women who had received the herbal intervention during the initial RCT experienced further reductions in VMS in the 48-week trial. Women who had received placebo initially experienced significant reductions in menopausal symptoms with the use of Siberian rhubarb. At the 48-week timepoint, hot flash scores were 8.9 ± 9.2 in the group that received the herb in the initial RCT, and 10.2 ± 8.6 in the group who had initially received placebo. During the 96-week follow up, symptom scores further decreased slightly (hot flash score 7.6 ± 8.0 in the initial herbal group, and 8.5 ± 6.9 in the initial placebo group). At 96 weeks, participants were having an average of <1.4 slight flushes per day. Again, there were no adverse events or safety concerns with longer use of the herbal supplement.⁴⁸

The same group of authors performed an additional clinical trial in 2009 to confirm the effects of Siberian rhubarb extract on VMS in perimenopausal women (N = 112). Women were randomized to either enteric-coated Siberian rhubarb extract, or a placebo, once daily for 12 weeks. Women who received the herbal extract experienced a significant reduction of MRS total scores (going from 27.0 ± 4.7 points at baseline to 12.4 ± 5.3 points at 12 weeks) compared to the placebo group (from 27.0 ± 5.3 points to 24.0 ± 6.2 points) (P < 0.0001). Siberian rhubarb supplementation also led to significant reductions in hot flash scores (P < 0.0001). Fourteen adverse events were reported in this trial: 11 events were reported by 5 women in the herbal group, and 3 events were reported by 3 women in the placebo group. Overall, Siberian rhubarb extract was well tolerated by the majority of subjects.⁴⁹

Red Clover Extract

The red clover plant, Trifolium pratense, is a widely distributed herb, native to Europe, Western Asia, and northwest Africa (and also introduced and widely found over North America). Red clover is well adapted to a variety of climates and soil types, and occurs both naturally and in cultivation.⁵⁰ Red clover extracts contain daidzein and genistein, but also have additional isoflavones not found in soy, such as formononetin and biochanin A.⁵¹ RCTs have generally demonstrated the safety and efficacy of red clover supplements for VMS, and a number of meta-analyses have also been performed. A summary of these studies is found in Table 1.

Table 1.

Meta-Analyses of Studies on Red Clover Extracts for Vasomotor Symptoms

Author	Subjects	Studies/Interventions	Outcomes
Ghazanfarpour (2016)	446 Perimenopausal and menopausal women	6 RCTs comparing red clover extracts to placebo. Doses of 40–80 mg/day of red clover for 4–12 weeks.	Red clover decreased mean hot flash frequency compared with placebo, close to but not at statistical significance (MD −1.99; −4.12 to 0.139; P = 0.067). In subgroup analysis, MDs were larger in postmenopausal women and in patients with higher frequency hot flashes (≥5/day) (P = 0.156 and P = 0.005, respectively).
Gartoulla (2014)	565 Postmenopausal women	8 RCTs comparing red clover extracts to placebo, at doses ranging from 40 to 160 mg/day, ranging from 3 to 12 months.	Compared to placebo, red clover extracts were effective at reducing VMS when taken for three to four months (P < 0.00001). However, this effect did not persist at 12 months (P = 0.07).
Kanadys (2021)	663 Perimenopausal and postmenopausal women	8 RCTs comparing red clover extracts to placebo, with doses ranging from 37.1 to 160 mg/day, with durations ranging from 12 weeks to 12 months.	Red clover reduced daily incidence of hot flashes compared to placebo (weighted MD −1.73 hot flashes/day, 95% CI −3.28 to −0.18; P = 0.0292). In subgroup analysis, MDs were larger in postmenopausal women with ≥5 hot flushes/day, with follow-up periods of 12 weeks, with isoflavone doses ≥80 mg/day, and with formulations containing higher proportions of biochanin A.
Myers (2017)	467 Postmenopausal women	5 RCTs of a specific standardized/proprietary extract of red clover at ≥80 mg/day, of 12 weeks' duration	Hot flashes decreased significantly with red clover extract at the 80 mg dose compared to placebo (weighted MD −3.63 hot flashes/day, 95% CI 2.70–4.56; P < 0.00001). Women were experiencing a mean of 7–12 hot flashes/day at baseline, so this represents a 30%–50% reduction in frequency.

CI, confidence interval; MD, mean difference; RCT, randomized clinical trial; VMS, Vasomotor symptoms.

These analyses demonstrated a variety of outcomes.^52

–55 Ghazanfarpour et al.'s results suggest that red clover extracts may perform best in postmenopausal women, and in those having higher frequency (≥5/day) hot flashes.⁵⁵ Gartoulla and Han's results indicated that red clover extracts are effective for VMS, but only in the short-term, that is, 12 weeks.⁵⁴ These results seemed consistent with Kanadys et al., which found red clover extracts to be more effective when used for 12 weeks, and in postmenopausal women with ≥5 hot flushes/day. Kanadys et al. also found that isoflavone doses ≥80 mg/day, and formulations containing higher proportions of biochanin A, were more effective.⁵³

The meta-analysis by Myers et al. seemed to have the greatest homogeneity of included studies, examining effects only in 12-week trials in postmenopausal women, using a standardized extract that has been shown to contain a higher proportion of biochanin A, at a dose of 80 mg daily. In this meta-analysis, women saw a 30%–50% mean reduction in hot flash frequency with red clover extract supplementation.⁵² Additional trials of longer duration would help answer the question of whether or not these effects on VMS are durable, or decrease over time, as suggested by the findings from Kanadys et al. and Gartoulla and Han.

Regarding safety, in a one-year clinical trial comparing a red clover supplement (containing 26 mg biochanin A, 16 mg formononetin, 1 mg genistein, and 0.5 mg daidzein) and placebo in 205 premenopausal, perimenopausal, and postmenopausal women (ages ranging from 49 to 65), the herb had no effect on mammographic breast density. In fact, mammographic breast density actually decreased in both the placebo and red clover groups, but the difference between the two was not statistically significant. Additionally, there was no effect on serum E2, FSH, or LH levels.⁵⁶ In an additional three-year study in women with a family history of breast cancer (N = 401), a red clover supplement (40 mg isoflavones daily) had no effect on bone density, mammographic breast density, or the endometrial thickness in postmenopausal women.⁵⁷

Black Cohosh

Black cohosh (Actaea racemosa or Cimicifuga racemosa) has a long history of traditional use for menopausal complaints, and is first mentioned in the medical and botanical literature in the 1700s.⁵⁸ Black cohosh is approved by the German Commission E as a nonprescription option for premenstrual, menstrual, and menopausal symptoms.⁵⁹ The root of black cohosh contains numerous bioactive constituents. These include triterpenoid glycosides, phenylpropanoid derivatives, and flavonoids. While black cohosh was initially assumed to be more directly estrogenic or to contain formononetin isoflavones, studies have failed to demonstrate an isoflavone content of black cohosh, or any activity on estrogen receptors.⁶⁰ Rather, evidence from both in vitro and in vivo studies points to a possible central mechanism, with the plant having serotonergic effects instead, or modulating the activity of thermoregulatory receptors.^58,60,61

Numerous trials have been conducted assessing black cohosh's effects on VMS. While a Cochrane review from 2012 failed to demonstrate a significant effect of black cohosh supplements on hot flashes in perimenopausal and postmenopausal women,⁶² updated or newer meta-analyses show positive effects.

In a 2021 meta-analysis, the effects of an isopropanolic C. racemosa extract were examined by pooling the results from 35 clinical studies and 1 additional meta-analysis, with a total of 43,759 participants, of which 13,096 received the herbal extract.⁶⁰

Black cohosh extract was found to be significantly superior for treating menopausal symptoms compared to placebo, with a standardized MD of −0.694 (P < 0.0001). Effect sizes were greater when higher dosages of black cohosh were given (suggesting a dose dependent effect), or when black cohosh was combined with St. John's wort (Hypericum perforatum) (MDs −1.020 and −0.999, respectively). In the placebo-controlled, double-blinded RCTs included in this analysis, significantly greater improvements in total MRS scores were seen with patients taking black cohosh extract for three months, compared to placebo (P < 0.001). Efficacy was best for the VMS domain of MRS, and with 0.03–0.05 MRS units, the effect size of black cohosh was similar to that seen with 0.6 mg conjugated estrogens. Benefits appeared to be highest among subjects starting black cohosh during the early climacteric phase. The included trials used varying doses of black cohosh extract, from 16 to 256 mg, for durations of two to six months. Black cohosh supplements were generally well tolerated, with few minor adverse events, and with the frequency of side effects being comparable to placebo.⁶⁰

In a 2023 random-effect model pairwise meta-analysis of RCTs, 22 studies with a total of 2310 menopausal women were included. Black cohosh supplements were found to significantly reduce both overall menopausal symptoms as well as hot flashes compared to placebo (P < 0.001 and P = 0.003 respectively). The dropout rate for black cohosh supplements was similar to that seen with placebo.⁶³

Turning to safety, in Castelo-Branco et al.'s 2021 meta-analysis described above, black cohosh had no hepatotoxicity, and no effect on hormone levels or breast or endometrial tissue.⁶⁰ Likewise, Naser et al.'s meta-analysis of 5 RCTs with a total of 1117 perimenopausal and postmenopausal women (40–60 years old) showed no effects on liver function. Subjects in included trials were treated daily with black cohosh (doses ranging from 40 to 128 mg) for periods of three to six months. There was no effect on liver transaminases in this analysis.⁶⁴ Treatment with black cohosh for six months has also been shown to have no effect on mammographic breast density, nor does it impact endometrial thickness.^65,66 Black cohosh supplements have also been used safely in at least six clinical trials in women with breast cancer, including those taking tamoxifen, raloxifene, or luteinizing-hormone releasing hormone analogues, at doses of up to 40 mg daily, for a period of up to 12 months.^67

–72

Discussion

The studies described above have found that these botanical medicines are both effective and generally well-tolerated among women with menopausal VMS. There are clearly a number of good options to choose from. When might one of these herbs be chosen over the other? Table 2 summarizes study findings for each botanical medicine explored in this article.

Table 2.

Botanical Medicines and Vasomotor Symptoms: Summarizing the Evidence

Flaxseed lignans	• Studies show flaxseed lignans decrease hot flashes, but reductions are similar to what is seen with placebo²⁵
Soy isoflavones	• Soy isoflavones shown to reduce hot flash frequency by 21% and hot flash severity by 26% compared to placebo; doses >18.8 mg genistein about 2 × as effective as lower doses.³² • Soy isoflavones may require longer periods of time to reach optimal effects. In one meta-analysis, 48 weeks of use was needed to see 80% maximal effect for hot flashes³³; in another, 16.6 weeks of supplementation was required for efficacy of soy isoflavones to surpass that of SSRI.³⁴
Red clover	• 30%–50% reduction in hot flash frequency seen with red clover extract at dose of 80 mg/day⁵² • Seems to work best in postmenopausal women, and in those having more frequent symptoms (≥5 hot flashes/day)^53,55 • Red clover extracts with higher proportions of biochanin A, and with isoflavone doses ≥80 mg/day, may be more effective.⁵³ • May be most effective when used for 12 weeks. Longer duration trials are needed to assess durability of effects.^53,54
Black cohosh	• Significantly reduces hot flashes compared to placebo^60,63 • In one meta-analysis, effect size of black cohosh was similar to that seen with 0.6 mg conjugated estrogens⁶⁰ • At least six clinical trials conducted in women with breast cancer.^67 –72
Siberian rhubarb	• The only botanical medicine described in this article that has not been the subject of either systematic review or meta-analysis • Subject of two RCTs (N = 109 and N = 112),^47,49 one of which was extended to 96 weeks duration⁴⁸ • Both RCTs indicated Siberian rhubarb was effective for hot flashes compared to placebo

SSRI, selective serotonin reuptake inhibitor.

The choice of one botanical medicine over another may depend on factors mentioned in the table (such as menopausal status, symptom severity, or how quickly relief of VMS is expected or needed). Keeping the whole person in mind, the clinician should also take into account the fact that the state of the patient's microbiome may impact the efficacy of phytoestrogen-based botanical medicines. For this reason (among others), a comprehensive approach to a woman's menopausal symptoms should of course incorporate a review of the patient's diet and digestive function, as well as other lifestyle factors.

Each woman's personal factors and preferences for addressing menopausal symptoms, including VMS, should also be taken into account during shared medical decision-making. Interest in or a preference for herbal medicines or other integrative therapies may be high in these patients. In the SWAN study, 80% of women utilized some form of complementary or alternative medicine (CAM) during the menopausal transition.⁷³ In another survey of midlife women (ages 45–57), 25% had used herbal medicines or natural products, and women with menopausal symptoms were about twice as likely to utilize CAM therapies.⁷⁴

This points to a need for healthcare practitioners to be well-versed in herbal therapies utilized for menopausal symptoms, with an appreciation and understanding of both safety and efficacy. None of the botanical medicines discussed in this article had effects on endometrial thickness or mammographic breast density, at least in the populations studied and for the durations mentioned. Incorporating botanical medicines into a woman's treatment plan during the menopausal transition may provide a special opportunity to engage her interests or preferences, and allow her involvement in creating a plan of care. The inclusion of botanical medicines along with lifestyle modification can represent an effective strategy to improve QOL in women undergoing the menopausal transition.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.▪

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