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Abstract & commentary
Synopsis: A double-blind, placebo-controlled trial of a relatively large dose of soy supplements could detect no effect on menopausal symptoms.
Source: Kotsopoulos D, et al. Climacteric 2000;3:
Kotsopoulos and colleagues from the monash Medical Centre in Australia randomized 97 postmenopausal women 50-75 years of age to soy supplements or placebo in a double-blind trial. The dose of isoflavones in the soy supplement given daily for three months was 118 mg. These women were experiencing a relatively high frequency of menopausal symptoms at baseline, although the severity was not extreme. The intake of soy protein was confirmed by demonstrating an increase in the urinary excretion of genistein and daidzein. No effect compared with placebo could be detected in vaginal dryness, libido, vasomotor reactions (hot flushes), psychological symptoms, or musculoskeletal complaints.
COMMENT BY LEON SPEROFF, MD
Phytoestrogens is a descriptive term applied to non-steroidal compounds that have estrogenic activity or are metabolized into compounds with estrogen activity. Phytoestrogens are classified into three groups: isoflavones, coumestans, and lignans. Soybeans are a rich source of phytoestrogens, containing the most common form of phytoestrogens, the isoflavones (mainly genistein and daidzein, and a little glycitein). Isoflavones exist in plants bound as glycoside conjugates attached at the 3 position, called glycones. The carbohydrate component requires gut bacteria to remove the sugar moiety to produce active compounds, the aglycones. Individual variability in gastrointestinal microflora, as well as absorption, influences the bioavailability of isoflavones.
You can eat soybeans every day and never see a bean. Soy flour is prepared to remove the carbohydrates. Nintey-five percent of soy flour is toasted and used as animal feed. Alcohol washing is used to get a taste-free product, but alcohol extraction removes the phytoestrogens. SUPRO from Protein Technologies International does not use alcohol extraction. SOYSELECT (Indena, Milan, Italy) and HEALTHY WOMEN (Johnson and Johnson, United States) are alcohol extracts. Oil and margarine have only traces of isoflavones; the conjugates are not soluble in oil.
The average Japanese intake of isoflavones is about 50 mg/d. Previous numbers were higher and were overestimated. The rest of Asia is about 25-45 mg/d, and Western consumption is less than 5 mg/d. A belief that Asian women report fewer menopausal symptoms is an underlying driving force in the promotion of isoflavones. However, this apparent difference in the prevalence of symptoms comparing Asia and the West may reflect cultural differences, not actual experience. It is important to keep in mind that the Cochrane Collaboration review of controlled trials found an average 51% reduction in hot flush frequency with placebo treatments. Therefore, studies of flushing without randomization to placebo treatment are not helpful.
An Italian study using SUPRO found a 45% reduction in flashing with 60 g of isolated soy protein daily (76 mg isoflavones), compared with a 30% reduction in the placebo group.1 Two other studies, both with 50 mg/d of isoflavones, found a similar 15% reduction in the number of flashes compared with placebo.2,3 In a randomized, crossover study of a high dose of isoflavones for flashes in breast cancer survivors, there was no effect.4 The dose was 150 mg isoflavones per day, similar to three glasses of soy milk daily. Why do these studies differ? It is unlikely to be a difference in dosing, in that the doses studied have ranged from 50 mg to 150 mg of isoflavones per day (the latter being a rather high dose). Perhaps the 15% difference compared with placebo observed in two studies reflects an effect on severe hot flushing, while mild-to-moderate hot flushing is not affected. However, a 15% difference is slight, and I suspect that clinicians would find it hard to observe this difference in an individual practice.
PROMENSIL is an extract of red clover (Trifolium pratense) containing formononetin, daidzein, biochanin, and genistein. Formononetin and biochanin are metabolized to daidzein and genistein, respectively. Red clover is a legume used to enrich nitrogen levels in soils. Promensil is produced by Novogen in Australia and marketed by Solvay in the United States. A 500 mg tablet contains 200-230 mg of dried aqueous-alcoholic extract; which contains 40 mg of isoflavones. The recommended dose is one tablet daily.
Two randomized, placebo-controlled studies of the effect of Promensil on hot flushes were reported in 1999, in Climacteric, the journal of the International Menopause Society.5,6 Neither demonstrated a significant difference compared with the placebo group. In one of the reports, four times the recommended dose (4 tablets daily) also had no effect.
I believe there is now sufficient evidence of appropriate quality to allow us to tell our patients that soy protein and isoflavone supplements do not help hot flushing. Any effect a patient experiences is a placebo response, not to be underrated, but certainly to be understood by the clinician and patient. In my opinion, there is only one medicine. Anything claiming to treat or prevent health problems must withstand the rigor of scientific studies of efficacy and safety. Anything with the potential to affect health must be subject to this requirement. The simplicity and correctness of this argument are so overwhelming, I believe it will come to be so.
1. Albertazzi P, et al. Obstet Gynecol 1998;91:6-11.
2. Scambia G, et al. Menopause 2000;7:105-111.
3. Upmalis DH. Menopause 2000;7:236-242.
4. Quella SK, J Clin Oncol 2000;18:1068-1074.
5. Knight DC, et al. Climacteric 1999;2:79-84.
6. Baber RJ, et al. Climacteric 1999;2:85-92.