Phytoestrogens: Natural Hormone Replacement Therapy?

Part I of a Series on Phytoestrogens

December 1998; Volume 1: 1-4

Are soy and flax safe, effective alternatives to hormone replacement therapy for treating menopausal symptoms? Asian women complain less of hot flashes than Western women, and it has been theorized that eating soy products serves as a type of dietary hormone replacement therapy.1 Several recent studies indicate that dietary supplementation with phytoestrogens (plant estrogens) does reduce hot flashes in some women; data on whether vaginal cytology improves are less convincing. Animal studies indicate that phytoestrogens may even reduce the risk of cardiovascular disease and osteoporosis, but there are no prospective human studies on these questions so far.

Phytoestrogens

The three main categories of phytoestrogens are lignans, isoflavones, and resorcyclic acid lactones. Soy products are high in isoflavones, which are also found in chickpeas and other legumes. Flaxseed, or linseed, is very high in lignans, which are found in whole grains, beans, vegetables, and fruits. Resorcyclic acid lactones are found mainly in fungi, especially Fusarium, that contaminate grains; these are not part of a normal diet and will not be discussed.

Phytoestrogens are weak estrogens; for example, the isoflavones in soy, genestein, and daidzein, are less than 1% as potent as endogenous estrogens in binding assays. Importantly, however, the biological activity of isoflavones is equivalent to estradiol at concentrations that elicit maximal responses.2 So, even though phytoestrogens bind weakly to receptors, in adequate doses they can elicit the same biological response as endogenous estrogens.

In Asia, consumption of legumes (e.g., soybeans, lentils, and peas) provides 25-45 mg of total isoflavones a day. In Japan, where soy consumption is especially high, up to 200 mg/d of isoflavones are consumed.2 In Western countries, average consumption is less than 5 mg/d. Soy products are not equal in terms of isoflavone content. (See Table 1.) Soy oil and soy sauce contain inconsequential amounts of isoflavones. Although fermented soy products often have lower amounts of isoflavones than unfermented products, fermentation appears to increase the bioavailability of isoflavones.

Table 1-Phytoestrogen Content Calculated from Results of Several Analyses
Isoflavones
Food No. of Foods Analyzed Daidzein, mcg/g Wet Wt. Genestein mcg/g Wet Wt.
Tofu 15 76 166
Soy sauce 3 8 5
Soy milk 10 18 26
Soy-based specialty formula 3 < 1 3
Soybean sprouts 3 138 230
Soybean, green 1 546 729
Tempeh 3 190 320
Soybean paste 6 159 171
Miso paste 2 266 376
Miso paste (rice or barley) 3 79 260
Soy hot dog, tempeh burger 2 49 139
Adapted from: Reinli K and Block G. Phytoestrogen content of foods—A compendium of literature values. Nutr Cancer 1996;26:123-148.


Clinical Trials of Soy and Hot Flashes

Three studies have shown that phytoestrogens can reduce hot flashes, and two of four studies have shown estrogenic changes in vaginal epithelial cells.

The most recent published study, performed in Bologna, Italy, was a randomized, double-blind, placebo-controlled study in 104 postmenopausal women.3 This study compared daily intake of 60 g of isolated soy protein to 60 g of the milk protein casein for 12 weeks. The soy-treated group had significantly fewer hot flashes compared to the placebo group. Women receiving soy experienced a 45% reduction in hot flashes, while the placebo group experienced a 30% reduction in hot flashes (hot flashes are a notoriously placebo-responsive condition). Significant differences between the two groups were observed by the fourth week. Adverse effects, mainly gastrointestinal complaints, were similar in both groups.

A 12-week study of 145 menopausal Israeli women (114 completed the study) found that the 78 women assigned to a phytoestrogen-rich diet had significantly fewer hot flashes and less vaginal dryness than the 36 women in the control group, who simply continued eating their normal diet.4 Total scores on a menopausal symptom questionnaire were not significantly different between the two groups. In this study, phytoestrogen intake (in the form of tofu, soy drink, miso, and ground flaxseed) constituted about one-fourth of daily caloric intake in the treatment group.

Another study in 58 women compared intake of 45 g of soy flour daily with 45 g of wheat flour for 12 weeks. The group supplemented with soy had significantly fewer hot flashes.5

Effect on Vaginal Epithelial Cells

Four studies have looked at whether supplementing the diet with phytoestrogens resulted in estrogenic changes in vaginal epithelial cells; two were positive and two were negative. A study in 25 women tested 45 g of soy flour daily and found significant improvements in the vaginal maturation index.6 The Brzezinski study also found improvements in vaginal cytology.4

However, the Murkies study did not find significant changes in vaginal cytology.5 Another study of 97 women (91 completed the study) found that administration of soy products (textured vegetable protein and dried soybeans for a daily intake of 165 mg isoflavones a day) resulted in an increase in the percentage of vaginal superficial cells in 19% of the soy group compared to 8% of controls; however, the results did not achieve statistical significance.7 This study apparently used an unusual method of collecting vaginal cells that may have underestimated estrogenized cells.2

Serum Hormone Levels

Phytoestrogens will not be picked up by conventional blood tests for estrogen levels; special assays for phytoestrogens must be done. While at least one study has shown a decrease in midcycle FSH and LH levels in premenopausal women (as well as an increase in the length of the follicular phase and delayed menses),8 FSH and LH do not seem to change in postmenopausal women. The Baird study showed no significant changes in LH, FSH, or sex hormone binding globulin (SHBG) between the soy-treated group and the control group (both groups showed slight decreases in LH, FSH, and SHBG).7 In the Brzezinski study, phytoestrogen supplementation in postmenopausal women markedly increased SHBG.4

Cardiovascular Disease Prevention

Soybeans may also have a beneficial effect on cardiovascular disease risk factors. In a meta-analysis of 38 controlled clinical trials on the effect of soy intake on serum lipids, ingestion of an average of 47 g of soy protein daily was associated with reduced cholesterol (23.2 mg/dL or 9.3%), reduced LDL cholesterol (21.7 mg/dL or 12.9%), and reduced triglycerides (13.3 mg/dL or 10.5%).9 HDL cholesterol was unaffected. In most studies, intake of fat, saturated fat, and cholesterol was similar between the control group and soy group, so lipid changes cannot be attributed to the lower fat content in soy products compared to animal products.

One primate study compared conjugated estrogens (Premarin) to phytoestrogens and found the two equivalent in affecting several cardiovascular risk factors.10 One hundred eighty-nine surgically menopausal cynomolgus monkeys were randomized into three groups and fed an atherogenic diet. One group also received soy with 1.7 mg/kg isoflavones; one group was supplemented with isoflavone-free soy, and the third group was given estrogen in a dose equivalent to conjugated estrogens at 0.625 mg/d (and a soy-free diet). The soy diet with isoflavones was equivalent to conjugated estrogens for most lipid and lipoprotein parameters; soy was superior in increasing apolipoprotein A-1 and in not causing an increase in triglycerides (a common side effect of conjugated estrogens). These investigators also found a beneficial effect of the soy diet (equivalent to conjugated estrogens) on coronary artery reactivity.

In a study of 22 atherosclerotic rhesus monkeys, all were fed a soy-based diet, but half of the monkeys received isoflavone-free soy while the others received isoflavone-intact soy.11 Quantitative coronary angiography was performed. Additionally, females in the low-isoflavone group underwent a second angiography after an intravenous dose of the isoflavone genestein. Arteries of males and low-isoflavone females constricted in response to acetylcholine, but arteries in the high-isoflavone group dilated in response to acetylcholine. Intravenous administration of genestein reversed the tendency of arteries to constrict in the low-isoflavone female monkeys. These reactions are similar to those caused by mammalian estrogens.

Osteoporosis

The effect of phytoestrogens on bone has not been well studied, but there is reason to believe that there may be some effect on bone. Asians have a lower rate of osteoporotic bone fracture than Western women, despite the fact that Asian women’s bones are thinner and their calcium intake is far lower than that of Western women. It bears noting that although soybeans are not naturally high in calcium, the process for making tofu (bean curd) involves the addition of calcium (magnesium may be used, but is far less common), so tofu provides significant calcium. (See Table 2.)

Table 2-Soy as a Source of Calcium
Mgs of Calcium
Tofu, firm,* 1/4 block (81 g) 553
Tofu, regular,* 1/4 block (116 g) 406
Soymilk, calcium-fortified, 1 cup 80-300
Soybeans, roasted, 1/2 cup 119
Soybeans, boiled, 1/2 cup 88
Tempeh, 1/4 cup 77
Soymilk, 1 cup 7
*Tofu processed with calcium sulfate
Chart source: USDA


In an animal study, soy protein isolate was equivalent to 17 beta-estradiol in preserving bone density in oophorectomized rats.12

Endometrial Cancer

Dietary phytoestrogen intake, unlike conjugated estrogens, does not appear to increase endometrial cancer rates. A multi-ethnic case-control study compared various dietary factors in 332 endometrial cancer patients in Hawaii and 511 age- and ethnicity-matched controls.13 This study included Japanese, Caucasian, Chinese, Filipino, and Native Hawaiian populations. High consumption of soy and other legumes was associated with half the risk of developing endometrial cancer (OR, 0.46; CI, 0.26-0.83; P = 0.01). High fiber and low-fat diets were also correlated with reduced risk.

Recommendations

For patients who do not want to take hormone replacement therapy, dietary supplementation with food products (such as soy products and flaxseed) is most likely safe and appears to alleviate hot flashes. Studies are mixed on whether there is a beneficial effect on vaginal epithelium. Whole grain breads and flaxseed breakfast cereal are good sources of lignans. Tofu, tempeh, dried soybeans, boiled soybeans, soy protein powders, isoflavone-enriched soy milk, and chickpeas (also called garbanzo beans) are all good sources of isoflavones. Low-fat soy products are available; the amount of fat (or protein) in a product does not affect isoflavone levels.

Isoflavone capsules are available. However, there are no human studies on the long-term effects of taking large doses of dietary supplements containing purified isoflavones, such as genestein or daidzein. It is unclear whether heavy intake of phytoestrogens in postmenopausal breast cancer patients would be beneficial or harmful. There are no data available on what interactions may occur when supplemental phytoestrogens are used concurrently with tamoxifen or raloxifene.

References

1. Adlercreutz H, et al. Dietary phytoestrogens and the menopause in Japan. Lancet 1992;339:1233.

2. Knight DC, Eden JA. A review of the clinical effect of phytoestrogens. Obstet Gynecol 1996;87(5):897-904.

3. Albertazzi P, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 1998;91:6-11.

4. Brzezinski A, et al. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4(2):89-94.

5. Murkies AL, et al. Dietary flour supplementation decreases postmenopausal hot flushes: Effect of soy and wheat. Maturitas 1995;21:189-195.

6. Wilcox G, et al. Estrogenic effects of plant foods in postmenopausal women. BMJ 1990;301:905-906.

7. Baird DD, et al. Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. J Clin Endocrinol Metab 1995;80:685-690.

8. Cassidy A, et al. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr 1994;60:333-340.

9. Anderson JW, et al. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;33:276-282.

10. Clarkson TB, et al. The potential for soybean phyto-estrogens for postmenopausal hormone replacement therapy. Proc Soc Exp Biol Med 1998;217:365-368.

11. Honore EK, et al. Soy isoflavones enhance coronary vascular reactivity in atherosclerotic female macaques. Fertil Steril 1997;67(1):148-154.

12. Arjmandi BH, et al. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr 1996;126:161-167.

13. Goodman MT, et al. Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol 1997;146:294-306.