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By Monica J. Stokes, MD, FACOG, ABHM
Menopause consists of a wide variety of signs and symptoms associated with acute withdrawal, or natural fluctuation and eventual diminution, of female reproductive hormones. This is superimposed on a background of progressive changes associated with aging. Medical problems may be initiated or exacerbated by withdrawal of the hormonal milieu associated with the reproductive age range.
Most animal and human studies regarding the health effects of soy are difficult to compare due to differences in the type of soy products used and the amount of isoflavone present. Despite this, it is clear that regular consumption of soy during the menopausal period may be helpful for some of the typical symptoms encountered. The use of soy beginning early in life or during early menopause also may be helpful for the prevention (and possibly the adjunctive treatment) of medical issues such as osteoporosis, some aspects of cognitive dysfunction, cardiovascular disease, and some cancers that may affect aging women.
Studies are ongoing to assess soy’s nutritional profiles and possible health effects in animals and humans.1 In addition, investigations are elucidating soy’s phytochemical pharmacokinetics and bioavailability,2 which should help determine which sources, purified extracts or food sources, will convey which specific benefits. Ultimately, these investigations will coalesce to determine which combination of constituents in soy exert which health benefits, and which individuals are likely to benefit most.3
In addition to soy protein, soy is a major source of the isoflavone class of phytoestrogens, consisting primarily of daidzein and genistein. It is thought that isoflavones act as weak estrogens, reversibly binding to estrogen-receptor isoform beta (ER-b) with greater affinity than estrogen-receptor alpha (ER-a). Isoflavones have been compared to selective estrogen-receptor modulators, in that they exert estrogen-like activity in some tissues, and no effect or anti-estrogenic activity in other parts of the body. ER-b receptors seem to be expressed more than ER-a in the central nervous system, the cardiovascular system, bone, and skin. ER-a receptors are in greater predominance in the uterus and breast. Isoflavones also may act via a number of non-hormonal mechanisms.
Equol was first identified in human urine in the early 1980s.4 Since that time, this metabolite of the isoflavone daidzein has demonstrated a more potent estrogenic potential than its precursor.5 There is considerable inter-individual variability in the metabolism of isoflavones including that of this bioactive, gut metabolite.6 Increased urinary excretion of equol in premenopausal women has been associated with a reduced risk of breast cancer.7 Equol excretors (equol-producers encompass about 45% of women) display different (favorable) plasma hormone profiles in comparison to non-excretors (non-producers). Equol excretor status may explain the variance regarding the biomarker and health benefits of soy in previous studies that did not consider this influence. Future isoflavone studies will likely control for this confounder. It will not be surprising if other bioactive metabolites of soy are identified in the near future.
The data regarding the benefit of soy for hot flashes and night sweats are mixed. Several studies have shown no benefit.8 The Soy Estrogen Alternative Study found no significant differences between soy protein alone or soy protein with two different moderate doses of isoflavones over a two-year period.9 This study chose perimenopausal women (likely having wide endogenous hormonal fluctuations affecting their symptom frequency), most with fewer than five hot flashes in a day, and more than 50% of the participants had previously used estrogen therapy, albeit more than three months before entering the study. The majority of studies, however, support a trial of soy foods or comparably dosed isoflavone extract supplements for the treatment of hot flashes and night sweats.10-12 In general, the expected degree of benefit is directly related to the degree of pretreatment hot flash frequency.13
In January 2004, the North American Menopause Society (NAMS) published a position statement on the treatment of menopause-associated vasomotor symptoms.14 Of the 15 randomized, double-blind (mostly placebo-controlled) trials reviewed in a section on isoflavones, only four studies demonstrated a significant decrease in hot flashes. Although acknowledging that the studies are difficult to compare due to differences in soy products used, and that the data on the estrogenicity of isoflavones are inconclusive, NAMS concluded that the potential for adverse effects is minimal with isoflavones from isoflavone isolates or food sources in the 40-80 mg/d dose range. (Interestingly, an individual’s intestinal equol production capacity does not appear to correlate with the degree of reduction of hot flash frequency obtained with soy consumption.)
In postmenopausal breast cancer survivors, Van Patten et al found that consumption of a soy beverage containing 90 mg of isoflavones over 12 weeks was no better than placebo in reducing the frequency of hot flashes.15 In a crossover trial using 114 mg/d of isoflavones in a similar population, similar results were obtained even when controlling for equol level status.
Vaginal Atrophy Prevention
In studies evaluating soy intake and improvement in vaginal cellular maturation index measurement as primary16 or secondary17,18 outcome, the results remain mixed with most studies finding no change during study periods of six months or less.
Osteoporosis: Soy and Ipriflavone
Soy foods and soy protein with and without isoflavones of varying doses continue to be studied to determine their role in the prevention and treatment of osteopenia and osteoporosis. High soy protein dosing, in contrast to high doses of animal protein, may have a less pronounced effect on renal calcium excretion, most likely related to an insulin-modulating effect on the kidney.19,20 Daidzein and genistein both suppress osteoclast activity, and genistein has been noted to have a stimulatory effect on osteoblasts in vitro as well as an anabolic effect on bone in animal models.21 Studies have produced conflicting reports on the effects of varying doses of isoflavones on markers of bone turnover.22 Collective data from in vitro, in vivo, human observational, and dietary intervention studies23 suggest that diets rich in phytoestrogens have bone-sparing effects in the long term. Soy isoflavones may offer the maximum benefit as a preventive intervention, not as a treatment for osteopenia and osteoporosis.
Ipriflavone is a synthetic derived from soy isoflavones. One ipriflavone metabolite, daidzein, undoubtedly contributes to its bone-sparing capacity (see Alternative Medicine Alert, December 2000). Ipriflavone has been found to have antiresorptive and possibly mild stimulatory effects on bone in the treatment of osteopenic and osteoporotic postmenopausal women (following urinary n-linked telopeptides, bone mineral density, and other measures of bone turnover, but few reported fracture endpoints).24 The bone-sparing effect is noted primarily at the lumbar spine, but has been shown to affect radial bone and femoral neck density as well. It has been shown to minimize glucocorticoid-25 and GnRH agonist-induced26 bone mass loss.
Ipriflavone currently is not recommended for use in pregnant or lactating women. It is to be used with caution in those with liver or kidney disease,27 and by those using theophylline (increased risk of toxicity).
A recently published, prospective four-year, randomized, double-blind, placebo-controlled multicenter study reported that ipriflavone may induce a slowly reversible lymphocytopenia in some patients.28 Renal and hepatic function, as well as lymphocyte counts (especially neutrophils), should be monitored during the first 6-12 months of treatment. The long-term effects of this dosing on the breast and female genital tract are as yet unknown.
The most common dosing of ipriflavone in published studies is 200 mg three times daily. The greatest bone-sparing benefit is obtained when taken concurrently with 1,000 mg/d of elemental calcium and 400-800 IU/d of supplemental vitamin D.
Genistein has been found to be comparable to 17b-estradiol in its anti-apoptotic properties on models of primary cortical neurons (rich in ER-b).29
The longest-running published trial was the Soy and Postmenopausal Health In Aging (SOPHIA) study, a methodologically sound study that looked at 56 cognitively intact women aged 55-74 years who were at least two years postmenopausal and not using hormone replacement therapy.30 The subjects were given 110 mg (a relatively high dose given divided in two daily doses) of extracted soy isoflavones or placebo daily for six months. The treatment group improved not only against their own baseline cognition scores, but were consistently better than the placebo group, especially in the area of verbal memory. As with estrogen administration, it is likely that the role for soy isoflavones is preventive, not therapeutic, in the maintenance of intact cognitive functioning during the aging process.
Heart disease remains the No. 1 cause of death in postmenopausal women. Despite this, public health messages (similar to efforts surrounding breast cancer awareness) regarding this fact have only very recently become more apparent in the media. Early, healthy dietary habit development and dietary interventions are two preventive strategies that must be employed to reduce the incidence of cardiovascular disease in women. Dietary soy certainly has a place in this effort.31
Soy isoflavones have been found to improve plasma lipids even in normocholesterolemic, premenopausal women throughout the menstrual cycle.32 Garcia-Martinez et al found that endothelial culture cells increase their ability to produce prostacyclin when treated with serum from postmenopausal women treated with isoflavones from soy and red clover.33 Steinberg et al found that daily consumption of soy protein with isoflavones had positive effects on vascular reactivity independent of lipid and antioxidant effects in healthy postmenopausal women.34
In a meta-analysis of 38 controlled clinical trials (men and women), Anderson et al examined the relation between soy protein containing isoflavones (25-50 g/d equivalent to 2-5 servings of soy foods per day) vs. animal protein consumption and serum lipids in humans.35 The authors concluded that significant reductions in total cholesterol, LDL-cholesterol, and triglycerides occur with soy but not animal protein, with the most profound effects noted in those subjects with the highest baseline levels. No significant changes in serum HDL-cholesterol levels were reported.
In October 1999, the Food and Drug Administration approved a food label health claim for reduced risk of heart disease on foods containing 6.25 g of soy protein per serving, assuming four servings, or 25 g of soy protein intake daily. Concurrently, the American Heart Association’s Nutrition Advisory Committee upgraded soy protein and isoflavones from its 1993 position, granting it a definite place in a heart-healthy diet, especially when used as a substitute for animal (highly saturated) fats and processed foods.36 Soy is particularly recommended for high-risk populations with elevated total and LDL-cholesterol. Citing Crouse et al, the American Heart Association recommends avoiding soy foods and concentrates that employ ethanol washing,37 which depletes isoflavone and possibly other bioactive soy component content, as there appears to be a dose-response effect of isoflavone content in soy and the degree of cholesterol-lowering effect.38 Due to the increased cardiac risk faced by diabetic postmenopausal women, soy use should be especially encouraged.
Low-dose soy supplementation does not appear to alter postmenopausal plasma hormone levels for estradiol, gonadotropins, prolactin, testosterone, sex hormone-binding globulin, or DHEAS.39,40 However, it has been suggested that even over a short term, soy consumption does appear to modulate endogenous estrogen metabolism in postmenopausal women, leading to a decrease in the ratio of negatively up-regulating and genotoxic estrogen metabolites (i.e., 16-a-hydroxyestrone and 4-hydroxylated catechol estrogens associated with breast cancer) to total estrogen levels. This suggests that soy constituents may exert cancer-preventive effects in postmenopausal women.41 Pharmacokinetic studies with huge single-dose administrations of purified soy isoflavones to postmenopausal subjects demonstrated that progressive accumulation with chronic dosing is unlikely.42
Genistein has been found to have a biphasic effect on the growth of MCF-7 cells in vitro with stimulation at low concentrations and inhibition at high concentrations. In animal models, genistein and soy protein have stimulated tumor growth in a dose-dependent manner and inhibited it.43 The estrogen status of the subject and/or the life-stage timing of administration44,45 may influence the combined effect of soy administration. The question of whether soy is protective against breast cancer or is harmful for women with a history of or at high risk for breast cancer remains unanswered.
Soy isoflavones, alone, have not been found to increase endometrial thickness.46,47 High-dose soy administration, as might be expected, does not act in a protective manner when matched against pharmacologic dosing of estradiol with respect to the endometrium. In recent randomized, controlled clinical trial (six months),48 soy protein isolate with 120 mg (high dose) of added isoflavones failed to block the effect of 0.5 or 1.0 mg of exogenous estradiol administration on the development of endometrial hyperplasia commonly associated with unopposed estrogen therapy in postmenopausal women.
Soy and Thyroid Function
One multi-ethnic, population-based, case-controlled study found that those with the highest quartile of soy-based food intake had the lowest risk for the development of thyroid cancer (odds ratio 0.65).49
A 1959 article by Van Wyk et al, in the journal Pediatrics, referenced rat data that showed that the goitrogenic effect of soy was blocked by iodine supplementation greater than the (at that time) recommended daily requirement. Since then, animal studies have shown that soy may stimulate T and B cell-mediated immune function. There is early speculation that in the face of certain background factors, such as iodine deficiency or the presence of other goitrogenic dietary (or possible genetic) components, constituents in soy (especially dietary genistein) might induce thyroid autoimmunity via inactivation of thyroid peroxidase.50 Given the high incidence of subclinical hypothyroidism in older individuals, this should be fertile ground for future study. In the meantime, it would be prudent to re-check thyroid function levels in those individuals with non-ablative hypothyroidism who begin incorporating soy products (regularly) into their diets to be sure no changes need to be made.
Available food sources include whole soybeans (fresh or dried), miso, soy protein powder, textured soy protein, soy flour, tempeh, soy meat alternatives, soy milk (often calcium- and vitamin D-fortified), and soy-fortified foods. The more processed the product, the more likely the depletion of the isoflavone content of the soy. While not all soy foods carry the soy protein or isoflavone content printed on their labels, foods that carry the heart health claim allowed by the FDA may now include the isoflavone or soy protein content claimed. In 2001, however, a study of 33 commercial phytoestrogen supplements and extracts revealed that there were considerable differences in the isoflavone content from that claimed by the manufacturers.51
In addition, concentrated encapsulated or otherwise powdered soy extracts (purified isoflavone or soy protein and isoflavone) are available; however, patients must be careful to avoid alcoholic extracts as they deplete the isoflavone content of the product. Patients also should avoid large doses (greater than 100 mg/d) of concentrated, extracted products until more is known about the long-term effects of these isolated products’ potential dose-related effects.
Ipriflavone, a synthetic isoflavone derived from the isoflavone classes found in soy, is also available. As described earlier, it has been studied primarily for its use for prevention of bone loss.
Studies cited in this paper have used a range from 20 mg to 125 mg of isoflavones per day. The American Heart Association recommends 25-50 g/d of soy protein with the caveats for avoidance of alcohol-extracted products to be sure the isoflavone content remains intact. Food-sourced consumption of less than 100 mg/d of isoflavones is likely safe in the long term. Patients should avoid excessive dosing with concentrated/ extracted products. Pharmacokinetic research suggests that separate servings during the day may be the best way to consume soy protein and isoflavones. It is as yet unclear whether this dosing is completely safe for breast cancer patients or those at high risk; however, one to two daily servings of soy foods is unlikely to be detrimental given current conclusions of research on this subject. For ipriflavone, the studies have used 200 mg three times daily for its bone-sparing effects. Consider the caveats noted previously if recommending its use.
Although we have many answers regarding soy, we have many more questions including the influence of age-related differences in exposure with health outcomes (perinatal, childhood, peripubertal, adult); timing of dosing with relation to intrinsic estrogenic state; differences in effects in different population groups (ethnic, metabolic, deficiency states, etc.); how to handle the high inter-individual variability in metabolism of isoflavones and of other, yet to be identified soy metabolites, or using these variables to our advantage to predict responses; and optimal dosing for specific health outcomes.
The possible adverse effect of various soy products on thyroid function awaits elucidation. The newer data regarding soy’s ability to modulate estrogen metabolism and equol production status are intriguing.
It seems reasonable to trial a soy protein isolate with isoflavones or soy foods for the treatment of hot flashes and night sweats in peri- and post-menopausal women. Due to the lack of long-term studies, however, it would be prudent to maintain the daily dose at or below 100 mg of isoflavones per day. It is only logical that whole-food soy sources will contain all of the possible bioactive constituents of soy as compared to extractions of only the currently recognized active factors. For breast cancer patients the safe dose of isoflavones has yet to be elucidated, and for most in this population it does not appear to be helpful for the treatment of hot flashes or night sweats. Until this issue becomes more clear, it would be prudent for women with a history of breast cancer to avoid extracted, non-food soy products, and limit intake to the heart-healthy recommendation level of 25 g of soy protein per day.
For general health, the data seem to support the regular inclusion of soy foods in all of our diets, especially when it is substituted for some of the animal fat and protein so ubiquitous in the Western diet. Dietary soy does not cause the loss of calcium through the urine that animal protein tends to encourage.
Dr. Stokes has a consultative holistic, integrative medicine, and women’s health practice in San Francisco, CA.
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46. Penotti M, et al. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril 2003;79:1112-1117.
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