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The onset of menopause marks a pivotal time in which the incidence of hypertension and cardiovascular disease begins to increase dramatically in women. Prior to menopause, the incidence of these diseases is significantly lower than in similarly aged men, but following menopause the rates rise rapidly until paralleling that in men. The loss of endogenous estrogen at menopause has traditionally been thought to be the primary factor involved in these changes and resulted in the widespread use of hormone replacement therapy (HRT) to reduce cardiovascular risk factors and decrease the affective symptoms of menopause. However, the adverse effects of HRT reported in recent large-scale trials (e.g., the Women’s Health Initiative) have greatly decreased the use of HRT by postmenopausal women.
Many women are seeking alternatives to HRT, including the use of dietary supplements that have a long history of use in traditional medicine, particularly in Asia. Examples of frequently used botanicals are soy, black cohosh, red clover, grape derivatives, St. John’s wort, Ginko biloba and Echinacea. While many of these botanicals appear to ameliorate some postmenopausal symptoms (i.e., bone loss, hot flushes/flashes and night sweats), none of the tested botanicals has proven as effective as HRT in decreasing the affective disorders of menopause. Further, despite the increasing usage of botanical supplements, their efficacy and safety have not been well documented by critical research studies. This review summarizes recent findings related to the utility of botanicals for menopause-related cardiovascular and metabolic disorders, specifically hypertension, diabetes, progressive cognitive decline and hyperlipidemia. While great caution should be exercised in the translation of animal findings to the human, these studies, along with those of others, suggest that some commonly used botanical supplements may be useful adjuvants for providing protection to women (and men) against cardiovascular risk.
Hypertension is a major health risk that significantly contributes to cardiovascular disease and stroke. Further, the incidence of hypertension increases with age, affecting approximately 30% of all adults and more than 60% of adults over 65 years of age (1). Persistent hypertension triples the incidence of heart disease and stroke and magnifies the adverse effects of other cardiovascular risk factors, e.g., smoking, type 2 diabetes, etc. (2;3). While most studies examining the mechanisms of hypertension have focused on men, it is clear that women also experience significant morbidity and mortality from effects related to hypertension, but there is a significant gender disparity in the incidence of hypertension and cardiovascular disease. Prior to menopause, blood pressure and cardiovascular disease is significantly lower in women than age-matched men. However, following menopause, the incidence of hypertension and cardiovascular disease increases dramatically in women, eventually approximating the incidence in men (4;5). While the mechanism underlying this increase is unknown, the loss of estrogen traditionally has been considered the primary factor.
The close correlation between estrogen loss and hypertension, cardiovascular disease, bone density loss and hot flashes made the use of hormone replacement therapy (HRT) commonplace throughout the last half of the 20th Century. The cardioprotective effects of HRT were supported by numerous basic research reports and clinical observations demonstrating a reduction of hypertension, atherosclerosis and cardiovascular disease in postmenopausal women on HRT. However, an increase in breast cancer rates in woman receiving HRT led some researchers to question the safety of the treatment. The Women’s Health Initiative and other contemporary studies further questioned the safety of HRT by demonstrating increased risk in thrombolytic events and heart attacks in HRT recipients. As a result, HRT has been strongly discouraged by most physicians and medical societies. The reported adverse effects of HRT have led many clinicians and users to seek alternative methods including the use of dietary supplements to provide the health benefits of HRT without the unfavorable effects.
While reports vary, most surveys suggest that over 50% of adults in the United States regularly take a dietary supplement (most frequently multivitamins), and about 33% of women of perimenopausal/postmenopausal age (45–60 years of age) regularly take some form of botanical supplement (6–9). The widespread use of supplements extends worldwide, where the majority of people rely on traditional medication (predominantly the use of plant extracts) for primary prevention/treatment of disease (10). The significant increase in US consumption of these supplements reflects increased desire for effective, safe, non-pharmaceutical therapies. Further, compliance with these treatments is better than that for most common pharmaceutical treatments, increasing their potential effectiveness when compared to drug therapies. While many of these supplements are taken for their presumed estrogenic actions, most of them appear to be only weakly or non-estrogenic.
Some of the most common botanicals used are soy, Ginko biloba, Kava kava, grape derivatives, Echinacea and black cohosh (7). However, the efficacy of botanicals as primary treatments for most diseases lacks basic and clinical research documentation. Botanical supplements appear to be useful as adjutants to pharmaceutical therapy and as preventative treatments, but the increasingly widespread usage of botanicals presents significant safety concerns. Botanical supplements are not as closely regulated as pharmaceutical products, and therefore, many may be adulterated with unexpected metabolites that could cause adverse reactions. Also, the concentration of active ingredients in botanical extracts can be very high compared to their concentration in whole plants, and therefore, toxicity may result from their ingestion. Further, the lack of basic and clinical research translates into an absence of reliable dosage guidelines. This problem is exacerbated by the belief that “if a little helps, a little more helps more” (11). Dietary intake of soy isoflavones chronically taken in excess (150mg versus 50 mg in Western diet or 100 mg in Japanese diet) can stimulate endometrial hyperplasia (12). A second more publicized example of adverse effects of botanicals relates to ephedra, which is a very effective weight loss dietary supplement for middle age and older adults. But it can have catastrophic results when younger adults take in it in large excess (13;14). St. John’s wort decreases depression in many users, but it also stimulates the pregnane X receptor and, thereby, alters hepatic metabolism of other pharmacological therapies (15;16). Similarly, Kava kava appeared to be an effective anxiolytic and to possibly exert a wide range of other heath benefits. However, hepatotoxicity linked to kava ingestion led to a ban on the botanical and careful consideration of its mechanisms of adverse action (17). Clearly, Kava kava is not hepatotoxic on its own, but increasing evidence suggests that its ability to alter drug metabolism in the body can lead to the serious side effects. Thus, supplements cannot be assumed to be safe just because they are “natural.” Even for the “safe” botanicals, one must be vigilant to both the beneficial and the adverse interactions between the botanical and diet.
Many of the botanicals display estrogenic-like binding and appeared to be promising for the alleviation of affective postmenopausal symptoms. Thus, studies have explored the potential of botanicals as alternatives to HRT for ameliorating hot flushes/flashes and night sweats. However, none of the tested botanicals has proven as effective as HRT. Black cohosh is the best candidate for alleviating these primary symptoms (18), but it remains very controversial since several large scale trials have not demonstrated any beneficial, postmenopausal effects, e.g., (19;20).
This review summarizes recent findings in relation to the utility of botanicals in other menopausal and aging symptoms, i.e., rise in arterial pressure, cognitive decline, insulin resistance and hyperlipidemia. While considerable caution should be exercised in the translation of animal findings to humans, several studies suggest that some commonly used botanical supplements may be useful adjuvants in reducing these symptoms.
Probably the most often studied and most widely used botanical in this category is soy. Due to the ability of its major isoflavones to bind estrogen receptors, it has often been considered a likely alternative to estrogen replacement therapy in postmenopausal women. Perhaps the best-documented effect of soy is its ability to lower plasma lipids. Dietary soy lowers LDL levels (21–28), triglycerides (24–27), and apolipoprotein B plasma concentrations (28). Soy may also increase HDL levels, although this increase appears to be negligible (29). The effects of soy on plasma lipids profiles do not appear to be gender specific (30). However, at least one study indicates a beneficial lipid effect only in hypertensive patients, versus normotensive patients, suggesting that its beneficial effects on lipids may be most active in compromised individuals (29).
Soy also has an ability to lower arterial pressure in postmenopausal women and in age-matched men, e.g., (31;32), similar to antihypertensive effects in animals, e.g., (33–35). Clinical data suggesting such a protective effect includes observations that dietary soy directly reduces arterial pressure in normotensive and hypertensive individuals. For instance in a randomized study of postmenopausal women, Welty, et al., (28) observed that dietary soy lowered systolic and diastolic arterial pressure in both hypertensive and normotensive individuals (28). Similarly, a clinical study by Teede et al. (30) demonstrated that three months of soy supplementation in normotensive male and female subjects significantly reduced systolic, diastolic and mean arterial pressure. Interestingly, in their follow up study they investigated the effect of soy supplementation on the same parameters in patients with established hypertension (36). In contrast to their previous findings, soy supplementation had no effect on any of the blood pressure parameters in hypertensive subjects, nor was there any beneficial effect on arterial function. This led them to propose that soy supplementation may be beneficial during the developmental but not the established phases of hypertension.
Other noted effects of soy include protective effects in heart disease (37;38), atherosclerosis of the carotid and coronary circulation in aged subjects (39–42) and stroke induced apoptosis (43). Dietary soy may also benefit diabetic individuals, as demonstrated by research showing that soy lowers fasting insulin levels, HbA1c levels insulin resistance, total cholesterol and cholesterol/HDL ratio, (44).
The most studied isoflavone constituents of soy are genistein and daidzein, both of which are structurally similar to estrogen and demonstrate binding affinities for the estrogen receptors (ER), primarily ER β receptors (11;45–47). This may account for their ability to specifically stimulate positive estrogenic actions while minimizing negative aspects related to estrogen (e.g,. enhanced cellular proliferation). The cardiovascular protective effects of soy isoflavones have largely mirrored those of soy, including improvement of blood lipid profiles (48–51). Soy isoflavone intake is correlated with a reduction in arterial pressure, both in clinical trials (52–54) and rat studies (55;56) and is reported to have a positive effect on bone density (57–59), endothelial function, cognitive performance and mood (60). Increased soy isoflavones have also been reported to potentiate protective effects of exercise on body weight and body mass index (51;57;58;61). The interpretation of these studies is complicated by the significant variability in isoflavone administration, e.g., use of different extraction procedures and different dosages. Thus, the intake of genistein and daidzein may vary significantly across studies (see).
Research in our laboratory has focused on the effects of soy isoflavones on blood pressure control in spontaneously hypertensive rats (SHR). SHR are a commonly used genetic model of hypertension, and exhibit a gender disparity in the degree of hypertension and salt-sensitivity exhibited. Male SHR display a pronounced elevation in hypertension as they age, and hypertension is exacerbated in response to dietary sodium intake (62;63). In contrast, arterial pressure is significantly lower in female compared to age-matched male SHR, and blood pressure is relatively resistant to dietary salt in female SHR (63). This suggests that estrogen exerts a protective effect on baseline arterial pressure and salt-sensitivity in SHR.
Based on evidence that dietary phytoestrogens (especially those from soy) could decrease cardiovascular and neuronal damage in animal models of disease (e.g., [64–67]), we explored whether phytoestrogens in normal commercial rodent diets (approximately 0.06% phytoestrogen, primarily from soy) played a protective role in blood pressure control. To test this, young female SHR were ovariectomized at 3 weeks of age and placed on one of four diets: 0.6% or 8.0% NaCl in the presence or absence of phytoestrogens (34). In SHR fed the phytoestrogen-free diet, the 8% NaCl diet caused a 68 ± 8 mm Hg increase in mean arterial pressure (MAP; figure 1). In contrast, in the phytoestrogen-replete diet, the 8% NaCl raised MAP by only 23 ± 4 mm Hg. In the ovariectomized SHR on the basal NaCl diet, elimination of phytoestrogen from the diet only slightly increased arterial pressure. Histological examination following 14 weeks on the diets demonstrated significant damage (frequent protein casts) in the kidneys of the high NaCl, phytoestrogen-free diet group but no appreciable damage in any other group. These data indicate that the elimination of all dietary phytoestrogens dramatically exacerbates the hypertensive effect of a high NaCl diet in young ovariectomized SHR (34).
Some studies have suggested that the beneficial effects of soy are dependent on the protein contained in soy or an interaction between the soy proteins and the isoflavones (68). To better define the role of soy isoflavones in female SHR, ovariectomized SHR were maintained on a phytoestrogen-free diet that contained 0.06% genistein which is approximately equal to the genistein content in soy-based rat chow and results in circulating genistein concentrations similar to that in Japanese women on a Japanese diet and in rats on normal chow diets. We observed that genistein supplementation significantly lowered the arterial pressure response to a high salt diet by about 50 mmHg, thus confirming the ability of specific soy phytoestrogens to blunt salt-sensitive hypertension (69).
While studies in young animals are informative, experiments in middle-aged animals are likely more instructive concerning mechanisms that underlie beneficial effects of isoflavones in postmenopausal women. We therefore examined whether soy isoflavones exerted similar protective effects in older animals. SHR were ovariectomized at 10 months of age (a stage in which their estrogen cycles are becoming irregular) and placed on a phytoestrogen-free diet, containing either basal or high NaCl diet. In the basal NaCl group, estrogen-depletion increased arterial pressure (12 mm Hg) and decreased norepinephrine release in the anterior hypothalamic nucleus, which is a sympathoinhibitory site (figure 2; ). The high NaCl diet increased arterial pressure by over 35 mm Hg, and this effect was reversed by estrogen replacement therapy, suggesting that both dietary NaCl excess and estrogen depletion raise arterial pressure in middle-aged female SHR by decreasing hypothalamic norepinephrine release.
We also examined whether phytoestrogens are similarly protective in stroke prone SHR (SHR-SP). Four-week-old female SHR-SP were ovariectomized or left intact and placed on a basal phytoestrogen-free or 0.06% genistein containing diet. Six weeks later, blood pressure and heart rate were recorded and norepinephrine (NE) was measured in the AHN. Intact and ovariectomized SHR-SP on a soy-based diet, did not display significantly different arterial pressures (70). In contrast, ovariectomized SHR-SP on a phytoestrogen-free (compared to soy-based) diet displayed a 34 mm Hg increase in arterial pressure and 90% reduction in AHN NE. The addition of phytoestrogens to the diet significantly blunted this decrease. Together, these data demonstrate that dietary soy isoflavones protect SHR-SP on a basal NaCl diet from hypertension and suggest that this effect is related to a isoflavone-induced increase in AHN NE release.
While our studies demonstrated that dietary soy isoflavones could blunt hypertension in female rats, it remained unknown if the dietary polyphenols could similarly protect male rats. Therefore, male SHR-SP were fed a basal (0.7%), medium (2%) or high (4%) NaCl diet with or without dietary phytoestrogens and blood pressure was monitored. The results demonstrated a positive correlation between salt intake and arterial pressure (figure 3, ) in male SHR on the polyphenol-free diet. However, in rats supplemented with genistein, the salt-induced changes in arterial pressure were eliminated. These data demonstrate that at least in this model of hypertension, soy isoflavones protect against salt-sensitive hypertension in both male and female rats.
To further probe the mechanism(s) underlying the beneficial effects of soy isoflavones, we investigated whether soy isoflavones reduce adrenergic receptor-mediated vasoconstriction in arteries of SHR, Wistar and Sprague-Dawley rats, using phenylephrine (PE; an α1 adrenergic receptor agonist) and acetylcholine (ACh; a potent activator of the NO-mediated vasodilation). In seven-week-old SHR on a basal NaCl diet, chronic estrogen depletion sensitized the vascular response to PE and desensitized the response to ACh. Acute (10 min) administration of genistein (<1 uM; equal to normal concentration of genistein in the plasma of rats fed a soy based diet) reversed these effects, decreasing the vasoconstrictor responses to PE and increasing the responsiveness to ACh. In SHR fed a high NaCl diet, responses to PE were sensitized by nearly a full log unit, and acute infusion of genistein returned PE responsiveness to control levels. The high NaCl diet also desensitized the vasodilator responses to ACh, and acute genistein infusion returned responses to basal conditions. Similarly, in both WKY and SD either the loss of estrogen or dietary NaCl excess favored vasoconstriction versus vasodilation and acute genistein pretreatment returned these responses to baseline (72).
While soy isoflavones have been a primary focus of clinical and basic research, they represent only a small portion of dietary polyphenols that are consumed. It is increasingly clear that less studied polyphenolic botanicals also have significant health-related benefits. The dietary sources of these are tremendously widespread (see ), and include polyphenols found in grapes and numerous other fruits, teas, chocolate/cocoa, and a significant number of vegetables and nuts. Of these, grape extracts and related red wine are some of the most studied polyphenolics (e.g., see [74–78]). Although the mechanism of grape seed polyphenols remains unclear, it appears that actions are mediated via non-estrogenic pathways. Grape seed extracts provide significant antioxidants and may reduce the amount of reactive oxygen species, which are elevated in cardiovascular and metabolic diseases.
Grape seed extract contains a high concentration of polyphenols, containing a rich mixture of monomeric flavan-3-ols (catechin and epicatechin), and oligomeric proanthocyanidins that display little to no estrogenic actions. Yet they appear to confer cardiovascular protective effects. Thus, we investigated the ability of grape seed polyphenols to reduce arterial pressure and salt-sensitive hypertension in estrogen-depleted SHR (79). Female SHR were ovariectomized at 3 weeks of age and placed on diets that were either devoid of polyphenols or were supplemented with grape seed extract (0.5%) and contained either a basal or high NaCl. After 6 weeks on the basal salt diet, grape seed supplemented SHR had a significantly lower arterial pressure than the SHR fed a non-supplemented diet (figure 4; ). On a high NaCl diet, grape seed supplementation (compared to non-supplementation) significantly blunted the rise in arterial pressure. Further, superoxide formation in the aorta of SHR fed a high salt diet was significantly reduced in the grape seed-supplemented group (figure 5). These results indicate that like soy phytoestrogens, dietary grape polyphenols are protective in estrogen-depleted SHR, but the effects of grape polyphenols appear to have different underlying mechanisms, e.g., a greater participation of superoxide scavenging.
There is clear evidence that hypertension impairs cognitive function, and that this relationship is positively correlated. Male SHR display an age-related decline in cognitive performance, beginning in the 10th–12th month of life. Although a similar fall in cognitive ability occurs in normotensive male rats, the onset is around 18 months of age. Female SHR also develop similar age-related deficits, albeit several months later than their male counterparts. Additionally, antihypertensive therapy attenuates the observed declines in cognition (80). We were interested in whether antihypertensive botanical supplementation would ameliorate cognitive decline in hypertensive rats. Female ovariectomized SHR-SP were fed a basal NaCl that contained 0.0% or 0.5% grape seed extract for 8 weeks, at which time cognitive abilities were assessed using an eight-arm-radial maze task. Although the grape seed extract did not lower arterial pressure in these rats, it did result in a significant improvement in the number of trials it took the rats to reach criterion performance (79). This indicates that grape seed polyphenols can positively impact cognitive function, although the mechanism may be independent of an effect on blood pressure, since the correlation between blood pressure and cognitive function was not significant.
In addition to soy isoflavones and grape seed extract, research from our laboratory is interested in the protective properties of extracts derived from the root of perennial leguminous vine Kudzu, or Pueraria lobota. Kuzdu was imported to the U.S. from Japan in 1876, and its high nutritional value, rapid growth and elaborate root system resulted in widespread usage in the southern United States for animal feed, soil enrichment and erosion prevention (81). While these uses eventually became supplanted by more efficient substances and techniques, Kudzu proliferated extensively and is now a highly invasive nuisance and threatens native plants. Kuzdu has an exceptionally long tradition in traditional Chinese herbal medicine, dating back to 200 B.C. (81). There are two components of Kudzu that are utilized in traditional medicine, including the flower, Flos puerariae, and root, Radix puerariae. While the most prominent use has been as amethystic (anti-alcohol intoxication) and antidipsotropic (anti-alcoholabuse) agents, uses also include cardiovascular and stroke protection along with antipyresis, antidiarrhetic and anti-emetic agents (81). While soy and Kudzu are both primary sources of polyphenols in Chinese medicine, the isoflavone compositions are markedly different. The principle isoflavanoid of Kudzu root is puerarin (daidzein-8-C-glucoside) and daidzein and genistein, are contained resent in low (1%–3%) concentrations (82). While daidzein and genistein act via estrogenic receptors, as discussed above, research has only started deciphering how puerarin exerts its effects. Reported actions of puerarin include stimulation of bone formation (83), is cytoprotective in rodent diabetic models (84), acts as a nerve growth factor (85), exerts a vasodilatory influence (86;87), and improves lipid profiles (88;89).
Probably the best studied effect of puerarin relates to glycemic control in diabetes. Hsu et al. (90) demonstrated that puerarin supplementation lowered baseline plasma glucose levels in Wistar Kyoto rats and had greater effect in streptozotocin models of diabetes. They also demonstrated that puerarin injections increased glucose uptake in skeletal muscle. These results suggest that puerarin improves glucose uptake in diabetic rats, and these actions may be extended into non-diabetic animals. A subsequent study by our group examined the role of puerarin on glucose control in ob/ob mice (91). Puerarin improved glucose tolerance in ob/ob mice. Interestingly, the effect of puerarin on glucose tolerance contrasted with that of daidzin, the next most concentrated isoflavanoid in kudzu. Daidzin had worsened glucose tolerance, i.e, compared to controls, plasma glucose concentrations reached higher peaks and took longer to return to baseline. These contrasting observations reflect the issue of potential conflicting components found in many botanical supplements. Similarly, we have also found that glycemic control is improved by both acute and long-term puerarin supplementation in both SHR-SP and mice (unpublished observations).
We have also investigated whether dietary kudzu supplementation protects against NaCl-induced hypertension in SHR, similar to that seen with other botanicals studied in our laboratory. Male SHR were maintained on a high NaCl, polyphenol-free diet containing either 0.3% or 0.0% kudzu extract. After 8 weeks on the diets, the arterial pressures were significantly lower in rats receiving kudzu root powder, suggesting that kudzu polyphenols blunt NaCl-sensitive hypertension in young, male SHR.
More recently we tested the ability of kudzu root extract to protect cognitive abilities. A previous report indicated that dietary puerarin decreased memory impairment in a mouse model of aging induced by D-galactose (92) and in ovariectomized female mice (93). Using a water maze task, we tested the hypothesis that dietary kudzu protects male SHR from a NaCl-induced memory impairment. Our data demonstrate that the kudzu root-supplemented rats displayed improved learning and memory abilities, relative to the non-supplemented group.
Research from our laboratory and others indicate that several botanical compounds have beneficial effects in humans and animal models of disease. While these compounds have had fairly limited success in relation to some of the more prominent affective symptoms of menopause, they appear more effective in relation to cardiovascular, metabolic and cognitive function. Thus, the health benefits of these compounds appear significant, but the safety and mechanisms of action of each should be carefully tested in relation to the disease status of potential users.
This work was supported by National Institutes of Health grants, AT 00477 (JMW) from the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements and NS 041071, NS 047466, the UAB Neuroscience Core Center NS47466 and the Alabama Neuroscience Blueprint Core Center NS57098 from the National Institute of Neurological Disorders and Stroke. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Complementary and Alternative Medicine, the Office of Dietary Supplements, or the National Institutes of Health.
The authors have nothing to disclose.