Alternative options for managing menopause

HRT is not the only option for postmenopausal women, however. Women who cannot or do not want to take hormones may decide to turn to natural remedies for managing their menopausal symptoms and risk factors. Indeed, non-pharmacologic therapies, including herbal treatment, are widely used but many remain relatively unstudied by the scientific community. A 1998 report indicates that 42 percent of adults have tried alternative medicines. And according to a 1993 survey of 1,539 adults, one in three respondents said they used at least one alternative therapy in the past year. The 1998 survey estimated that out-of-pocket expenditures for alternative therapies totaled $27 billion a year. The amount is comparable to that spent for all U.S. physician services.

Isoflavones and menopause management
Observational data provide evidence that an isoflavone-rich diet may not only reduce the prevalence of acute menopausal symptoms but may also lower the risk of hormonerelated cancers. Of the broad range of estrogenic substances in plants (phytoestrogens) the isoflavones have the most potent estrogenic activity. Although not as potent as 17ß-estradiol, in populations with high legume intake isoflavones may be present in the body at levels up to 1,000 times those of steroidal estrogens. They compete with endogenous estrogen for receptor sites and if endogenous levels are high, isoflavones may exhibit anti-estrogenic properties. If endogenous levels are low, as in menopausal women, isoflavones may exhibit estrogenic properties.

Like the synthetic estrogen antagonists tamoxifen and raloxifene, isoflavones appear to possess tissue selectivity in their agonist and antagonist effects. This effect is explained by the existence of two types of estrogen receptors—alpha and beta. Alpha receptors are the main receptors in the breast and uterus and beta receptors are mainly found in bone and the cardiovascular system. Estradiol has affinity for both receptors whereas the isoflavones are more selective for beta receptors. Isoflavones are found mainly in plants of the legume family and four isoflavones have been described. Whereas the soya plant contains only genistein and daidzein, other legumes like chickpeas, lentils and alfalfa sprouts contain biochanin and formononetin, but the red clover plant contains all four.

The majority of plant isoflavones exist in the form of glycosides; that is, they are attached to a sugar molecule. To become biologically available these glycosides must be cleaved in the gut to yield a sugar-free aglycone. After conversion to the aglycone, about one-third is absorbed as free isoflavones and the remaining two-thirds are fermented by bacteria in the large bowel into metabolites such as equol, which are then absorbed.

Asian diets and isoflavones
Interest in isoflavones followed observations that Asian women, who consume more isoflavones than Western women, experience fewer menopausal symptoms.

A study of menopausal Thai women, for instance, demonstrated that only 27 percent experience hot flashes and 24 percent report nights sweats. In contrast, up to 85 percent of Western women experience vasomotor symptoms. A study of Japanese women also found lower incidence of vasomotor instability among them compared with Western women.

While these epidemiologic studies do not establish a cause and effect relationship, the lower incidence of climacteric symptoms may be attributable to diet rather than genetic disposition —a theory supported by a review article showing that Asian people who consume more Western diets have a higher risk of chronic and degenerative disease, including hormone-dependent cancers, colon cancer and cardiovascular disease, compared with those who consume traditional Japanese diets.

Researchers began to suspect that isoflavones were the beneficial substance because they are found in abundance in East Asian diets. One study found that the excretion of isoflavonoids in urine was much higher in Japanese women than in American and Finnish women. Food sources of isoflavones include legumes, especially soy and soy products like tofu, sweet potatoes, carrots, garlic, red wine, barley, green beans, oats and pumpkin.

Effect of isoflavones on acute symptoms of menopause
A number of studies have been conducted on the effect of isoflavones on hot flashes, the commonest menopausal symptom. Some suggest these phytoestrogens impart benefits and others do not. The final results of one randomized, double-blind trial of a red clover isoflavone extract, for example, concluded that “there was no significant difference between active and placebo groups in the reduction in hot flashes . . .�?during a three month period.

This result may have been confounded due to protocol violations by women in the placebo group who introduced isoflavones into their diet as evidenced by their presence in the urine collected at the final study visit. However, analysis of pooled data from all subjects regardless of treatment group at week 12 revealed a statistically significant correlation between the reduction in hot flashes and urinary isoflavones excretion, with all subjects with urinary isoflavones excretion greater than 2 mg per day reporting a reduction in hot flashes greater than the placebo response. This indicated that as isoflavone intake increased there was a greater reduction in hot flashes.

A second randomized, double-blind trial of the same proprietary red clover-derived isoflavone preparation (Promensil; Novogen Ltd, Australia), given at a dose of 40 mg per day, produced a 75 percent reduction in hot flashes after 16 weeks in 30 women. The difference between placebo and isoflavones groups was significant (p<0.001). A similar open trial using the same red clover extract reported significant improvements in hot flashes and night sweats.

Effect of isoflavones on osteoporosis
Studies of the effects of isoflavones on bone health have produced mixed results. According to two multicenter studies, the synthetic isoflavone ipriflavone prevents bone loss in postmenopausal women with low bone mass. Four hundred and fifty-three women were given either 200 mg of oral ipriflavone three times a day or placebo for two years. All of the women were also given 1 g of calcium daily. In both studies, the ipriflavone group maintained bone mass, whereas the placebo group experienced a decrease in bone mineral density. Overall there was a bone-sparing effect of 1.6 percent in one study and 3.5 percent in the other with ipriflavone. The synthetic isoflavone prevented both axial and peripheral bone loss and was well tolerated. However, in a more recent study no effect of ipriflavone on bone density was observed and adverse hematological effects were reported.

Recently data has been presented on a year-long, double-blind placebo-controlled study involving 107 women showing that 40 mg of red clover isoflavones decreased the rate of loss of bone mineral density (BMD) and bone mineral content (BMC) in lumbar spine of pre- and peri-menopausal women. No differences were seen between treatment groups in hip BMD, BMC or urinary bone markers.

Similarly, a study using Rimostil, which contains the proprietary isoflavone blend Clovone (Novogen Ltd, Australia), found that this supplement increased BMD in the proximal radius and proximal ulna, implying that these isoflavones have significant estrogenic activity in bone. The compound did not cause uterine bleeding or any significant changes in endometrial thickness.

Other research has shown that bone density increases in women consuming soy enriched bread, compared with a control group eating wheat bread.

Isoflavones and cancer A review of the clinical, epidemiological and mechanistic evidence indicates that isoflavones may possibly have anti-carcinogenic effects. Tham and colleagues cite studies, for instance, that suggest phytoestrogens may reduce breast and endometrial cancer risk. Another study found a reduced risk of breast cancer in women with elevated urinary isoflavones. The investigators noted that some researchers have postulated that isoflavones may act as anti-estrogens by competing with estradiol for binding sites, thereby inhibiting the growth of hormone-dependent cells. They may also stimulate SHBG in the liver, thus reducing the amount of “free�?estradiol in the plasma.

In a review of five other studies on soy and breast cancer risk, three suggested an association between reduced risk for premenopausal breast cancer and soy. The fourth study was the only one that showed a decreased risk of postmenopausal breast cancer, whereas the final study found a nonsignificant decrease in breast cancer risk associated with tofu intake. In contrast, another study reported the cytologic detection of epithelial hyperplasia in 29 percent of women receiving soy supplements for six months. This suggests that prolonged intake of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells and elevated plasma estradiol. However these data were from a pilot study which did not include a control group and the conclusions need to be confirmed by further research. The potential mechanisms for these epidemiological observations are multiple.

Isoflavones have been described as having anti-cancer activity against various types of human and animal cancers. Known biological effects of these compounds which may contribute to their anti-cancer action are (a) modulations of signal transduction mechanisms through inhibition of enzymes such as protein tyrosine kinases and DNA topoisomerases I and II, (b) interruption to cell cycle kinetics by blocking cells in the G2/M phase of mitosis, (c) induction of terminal differentiation of cancer cells, (d) inhibition of enzymes involved in the synthesis of androgens (inhibition of 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase) and estrogens (inhibition of aromatase), (e) possession of natural antioxidant activity, (f ) induction of apoptosis in cancer cells, (g) inhibition of angiogenesis, (h) estrogen receptor antagonism and (i) promotion of cancer cell adhesion.

Potential clinical use of isoflavones in menopause management
Safe and effective alternatives to HRT would be a welcome addition for the treatment of menopausal symptoms and to improve cardiovascular health and slow the rate of bone loss. There is now a substantial body of evidence to suggest that isoflavones offer benefits but more interventional trials are required to reach definitive conclusions.

Isoflavones derived from red clover have been shown in controlled studies to have a positive impact on bone density, cholesterol profiles and on arterial compliance. Epidemiologic studies suggest that an intake of more than 40 mg a day of isoflavones has some protective effect against cancers. Also positive is the low side-effect profile with a lack of stimulating effect on endometrial and breast tissue in studies to date. The evidence pointing to a therapeutic effect on menopausal symptoms like hot flashes is mounting but further proof is needed with larger controlled studies. For women who do not want to take estrogen, isoflavone-containing foods may provide some benefits but it is unlikely that foods can offer an adequate alternative for women seeking estrogen’s full and welldocumented benefits: protection against heart disease and osteoporosis. If despite estrogen’s proven advantages, a patient decides to choose the isoflavone approach over HRT, she needs to realize that it would be difficult to obtain the needed dosage from diet alone. Certainly caloric intake would have to increase significantly to do so. Standardized supplements would probably be required.

Editor’s Note: Research indicates men also benefit from dietary estrogens and the incidence of both benign prostatic hyperplasia (BPH) and prostate cancer are markedly reduced in countries where high legume intake is practiced, due in part to the hormone balancing effect of plant estrogens (anti-androgen action) and the inherent ability of isoflavones to act as inhibitors of 5 alpha-reductase, the enzyme which converts testosterone into the more potent dihydrotestosterone. It is also possible that the cardiovascular benefits which women experience after estrogen supplementation can be achieved in men.

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Lila E. Nachtigall, M.D. is a professor of obstetrics and gynecology at the New York University School of Medicine. Dr. Nachtigall is the president of the North American Menopause Society. From:  www.americanwellnessnetwork.com