In developed nations, the leading overall cause of mortality in women is coronary artery disease (CAD), (1) with the risk of the disease increasing dramatically after menopause. The hypothesis that loss of estrogen is the cause is supported by studies of younger women who are postmenopausal due to surgery. (2) In an effort to combat CAD, many postmenopausal women were placed on an estrogen replacement therapy regimen using conjugated equine estrogens believed to provide a wide spectrum of beneficial cardiovascular effects, such as:

• relaxation of precontracted smooth muscle cells
• inhibition of calcium entry
• enhancement of nitric oxide synthase reactivity
• stimulation of prostacyclin
• prevention of myointimal hyperplasia
• endothelium-dependent vasodilation of coronary and brachial arteries.
  

However, newer clinical studies have shown that that this "magic bullet for menopause" not only failed to live up to its earlier promise, but also is responsible for concomitant adverse effects, ranging from hypertriglyceridemia, endometrial hyperplasia, tumorigenesis, and hypercoagulable states. In fact, the National Institutes of Health (NIH) discontinued several phases of the now famous Women's Health Initiative (WHI) study (3) because the risks of hormone therapy, including estrogen-only therapy and combined estrogen plus progestogen therapy, far outweighed the documented benefits associated with these hormones.

Data from the discontinued estrogen-only study showed that estrogen not only had no effect on preventing heart disease after seven years of continuous use but also increased the risk of stroke, with a separate report pointing to "probable" dementia and/or mild cognitive impairment associated with estrogen-alone therapy. (4,5) The combined estrogen plus progestogen therapy also failed to live up to its promise. While it did prevent the stimulation of endometrial hyperplasia, it failed to provide lipid-lowering effects. (6) In addition, synthetic progestins presented an even greater risk of breast cancer than estrogen alone (7) and increased the risk of stroke, heart attacks, and blood clots in legs and lungs. (8) Fortunately, there are now other options available to women that afford cardioprotection and have a consistent safety profile.

Bioidentical Hormone Therapy
Since the 1930s, synthetic estrogens have been used to alleviate the major menopausal symptoms, with synthetic progestins becoming part of the therapy in the 1980s to counter the dramatic rise in uterine cancer that was related to estrogen-only treatment. (9) With the advent of bioidentical/natural hormone replacement therapy (BHRT), women now have a viable option that will alleviate menopausal symptoms while providing the cardiovascular protection formerly provided by their body's own hormone supply. The therapy uses hormones derived from a range of sources, including plants (phytoestrogens) as well as dehydroepiandrosterone, pregnenolone, cortisol, growth hormone, estradiol, estrone, and estriol, along with natural progesterone and testosterone, if needed.(10)

[ILLUSTRATION OMITTED]

The importance of using a natural hormone, like natural progesterone, for example, versus synthetic progestins is twofold. First, research (11) has shown that progesterone can inhibit the change of cholesterol into cytoplasmic cholesteryl ester (CE) (a crucial early step of atherogenesis, more commonly known as "hardening of the arteries") and decrease CE macrophage cellular levels. Second, natural progesterone can also block the increase of CE accumulation in macrophages. Unfortunately, this beneficial effect can be inhibited by synthetic progestins, demonstrating the importance in developing remedies derived from nature rather than synthesized in a laboratory environment.(12)

Cardioprotectants in Women: Whole Grains, Fruits, Vegetables, and Plant-Based Phytoestrogens
In addition to utilizing BHRT to address both menopausal symptoms and the increased risk of cardiovascular disease that can accompany them, women can also gain a level of cardioprotection from specific dietary choices--specifically, whole grains, plant-based phytoestrogens, fruits, and vegetables. This is especially important when other cardiovascular risk factors, such as hormone replacement therapy (HRT) use, smoking, alcohol consumption, saturated and trans-fatty acid intake, and sedentary lifestyle, exist.

Whole Grains and Ischemic Stroke
Various studies (13) have demonstrated the inverse association of the intake of whole grains and the risk of ischemic stroke and ischemic heart disease (IHD) among women. In each case, whole grains provided a significant benefit unmatched by refined and total grain intake. For example, in the Iowa Women's Health Study, (14) involving 34,492 women, there was a one-third reduction in IHD risk noted during a nine-year follow-up period--even after controlling for many confounding variables such as dietary fat and cholesterol--which correlated inversely with whole grain intake.
Also supporting this theory are the results of a ten-year study (part of the Nurses' Health Study) (15) involving 75,521 female nurses aged 38 to 63 years, none of whom had a previous history of coronary artery disease, stroke, diabetes mellitus, or other cardiovascular diseases at the time the study began in 1984. During the twelve years, only 352 confirmed cases of ischemic stroke were reported, which, based on the detailed food diaries kept, demonstrated an inverse relationship between whole grain intake and ischemic stroke risk.(16)

Researchers attribute this reduced chronic disease risk to the many phytochemicals, including fiber and antioxidants, contained in whole-grain foods but absent in refined grains. Interestingly enough, although there is a significant amount of Vitamin E, folate, and fiber found in whole grains, they are not considered to be a major factor in inhibiting IHD, which further demonstrates the cardio-protective nutrients of the other components found in whole grain foods.

Phytoestrogens and Cardiovascular Disease Risk in Women
Phytoestrogens are also effective in reducing the risk of cardiovascular disease. And, unlike synthetic estrogen replacement, they come without harmful side effects such as increased blood coagulability and risk of breast and uterine neoplasms. (17,18) Their success can be attributed to their structural resemblance to mammalian estrogens (19) which, by eliciting a weak estrogenic response, (20) binds estrogen receptors in vivo, thereby blocking the more potent activity of endogenous estrogens, including the triggering of abnormal cell growth (e.g., hormone-sensitive cancers).

Among the positive effects of phytoestrogens is their ability to:

• lower LDL cholesterol without hypertriglyceridemia
• reduce menopausal symptoms without an associated increase in risk for uterine and breast neoplasms
• enhance vascular function without an acceleration of pathological angiogenesis.

A research review (21) of the main studies published to date on the efficacy of phytoestrogens in reducing the symptoms of menopause concluded that a diet rich in phytoestrogens (90 mg/day for at least six months) is associated with a reduced incidence of vasomotor episodes and reduced levels of total and LDL cholesterol. In addition to these cardiovascular benefits, ingestion of phytoestrogens also results in an increase in bone mineral density (BMD) and a possible reduction in the risk of breast cancer.(22)

Lignan-rich foods also have an inverse relationship to body weight, specifically the waist-to-hip ratio, which, when high, is one of the markers for increased cardiovascular risk. When researchers(23) conducted a cross-sectional study involving 939 postmenopausal women, they found that those who consumed more phytoestrogens had less weight in their midsection, which translates to lowered cardiac risk. Sources of phytoestrogens include soy and red clover isoflavones, lignan precursors found in cereal seeds such as flax and sesame; plant sterols; and coumestans (a subcategory of phytoestrogens found in peas, beans, and a wide variety of vegetables), which may also have anticancer effects.

Flaxseed
Flaxseed, the richest known source of plant lignans (a sub-class of phytoestrogens), has been shown to have cardioprotective and chemoprotective effects in postmenopausal women. When digested, the lignan precursors matairesinol and secoisolariciresinol found in flax yield the active lignans enterolactone and enterodiol, which have the above-mentioned beneficial impact on the cardiac system.(24)
Flaxseed may also serve a significant role in the fight against breast cancer. When researchers(25) examined the effects of flaxseed consumption (5 to 10 g of ground flax per day) on urinary estrogen metabolite excretion in postmenopausal women, they found an increase in urinary 2-hydroxyestrone excretion. Since levels of urinary 2-hydroxyestrone are one of the biomarkers indicating a reduced breast cancer risk, this ability to increase the excretion rate of the metabolite illustrates flaxseed's potential chemoprotective ability.

Red Clover and Properly Prepared Soy
Both red clover and properly prepared soy represent safe and natural preventives for heart disease and, like other phytoestrogens, have not been linked to increased blood clot-related events. In fact, study results(26,27) indicated a significant, dose-dependent improvement in systemic arterial compliance in menopausal women receiving purified red clover and soy isoflavones nearly to the extent observed with estrogen replacement therapy.(28-30)

The wild legume red clover is high in several isoflavones, particularly biochanin A and formononetin, precursors of genistein and daidzein, respectively (both of which are also present in soy).(31) Research has indicated that genistein may have some role as a chemopreventive agent against cancer in humans,(32) while daidzein has been found to improve cholesterol and triglyceride levels in women.(33) While a study by Howes et al.(34) found that isoflavones from red clover had no significant effect on cholesterol in moderately hypercholesterolemic postmenopausal women, it failed to take into account the impact of all isoflavones present in the legume. Other compounds found in both red clover and soy, such as saponins, peptides, and globulins, also provide beneficial actions. For example, saponins can decrease blood cholesterol by enhancing the fecal excretion of bile.(35)

Antioxidants by nature, isoflavones possess the ability to inhibit the oxidation of LDL cholesterol,(36,37) which makes them a valuable ally in the battle against heart disease,(38,39) as illustrated by a 24-week study (40) involving the use of soy protein containing natural isoflavones. Sixty-six hypercholesterolemic, menopausal women first followed a two-week basal, low-fat, low-cholesterol diet and then were assigned one of three diets: a casein and non-fat milk (the control group), a soy protein with moderate isoflavone content (ISP56: 56 mg aglycone form/day), or soy protein with high isoflavone content (ISP90: 90 mg aglycone form/day) as the protein source.

Relative to the control group, women in both soy groups had significantly lower non-HDL cholesterol, although the total cholesterol was unchanged. HDL cholesterol increased significantly in the soy groups, thereby lowering the ratio of total to HDL cholesterol, while the casein group had significantly decreased HDL cholesterol levels relative to pre-trial levels. It has been reported that for every 0.026 mmol/L increase in HDL, the risk for coronary artery disease is reduced by three percent in women.(41)

Mononuclear cell LDL receptor messenger RNA increased significantly in both soy groups as well, suggesting a possible mechanism for the cholesterol-lowering effects of soy protein. Apolipoprotein-B containing LDL is probably depressed by a mechanism involving increased LDL receptor quantity or activity. Other studies support the role of LDL receptor activity in reducing cholesterol,(42,43) while other mechanisms include an increased excretion of bile acids, thereby enhancing removal of LDL and initiation of a hyperthyroid state that elevates free thyroxine after soy feeding.

Isoflavones can also combat hyperlipidemia (high lipid or fat levels in the blood), as illustrated by a study of mice fed a high cholesterol diet, with part of the group also given supplemental isoflavones. The former showed evidence of hyperlipidemia, suggesting that isoflavones support augmented receptor-mediated LDL and VLDL cholesterol removal by hepatocytes.(44)

It is critical to note that, similar to the conclusions comparing the performance of whole grains to refined grains, intact soy protein has been shown to reduce cholesterol concentrations to a greater extent than isolated amino acids patterned after soy. This illustrates once again the importance of choosing phytoestrogen sources that include all the active components.(45)

Fruits and Vegetables
In addition to the traditional lipid panel that measures LDL, HDL, and triglyceride levels, levels of C-reactive protein (CRP) and homocysteine, markers of inflammation, are now being tracked, since they have recently been associated with atherosclerosis. Once again, Mother Nature steps into the fray, providing at-risk patients with natural sources--in the form of fruits and vegetables--to combat this condition. Studies have shown that a significant amount of both fruits and vegetables in the daily diet can result in decreased plasma CRP and homocysteine levels.(46-48) Serum folate levels rise simultaneously with the fall in these inflammatory markers,(49) which may, in part, be a direct result of ingesting foods rich in that vitamin.(50)

Conclusion
It's evident that women seeking solutions to menopause symptoms and the increased cardiac risk associated with that physiological life stage would be better served by choosing bioidentical hormone therapy and natural food-based remedies such as whole grains, soy and other plant-based phytoestrogens, and fruits and vegetables. Nature provides comprehensive solutions that pharmaceutical companies thus far have been unable to emulate without associated risks.

© COPYRIGHT 2006 Dr. Gina Nick

References

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