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ORIGINAL RESEARCH |
From the Menopause and Osteoporosis Center, University of Ferrara, Ferrara, Italy; Departments of Statistics and Obstetrics and Gynaecology, Bologna University, Bologna, Italy; and Tenovus Cancer Research Centre University of Wales, College of Medicine, Cardiff, Wales, United Kingdom.
Address reprint requests to: Paola Albertazzi, MRCOG Strada Maggiore 14 40125 Bologna Italy
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Abstract |
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Methods: Phytoestrogen levels in blood and urine were correlated with the number of hot flushes and vaginal maturation indices in 104 postmenopausal women whose diets were supplemented with 60 g of soy powder daily for 3 months in a double-masked, parallel, placebo-controlled trial. The effect of soy supplementation on menopausal symptoms in this study population was reported previously.
Results: Serum levels of genistin, daidzin, and equol were significantly higher in women after soy diet supplementation (+756%, +593%, +1008%, and 57% respectively). The concentration of enterolactone in the soy group was increased by 57% compared with baseline, but the difference with placebo was not statistically significant. The increase in phytoestrogen levels in the soy group in blood or urine did not correlate with fewer hot flushes. Vaginal maturation indices did not change in the soy group.
Conclusion: Phytoestrogen levels increased in women who consumed soy supplement, but that does not fully explain climacteric symptom reduction. It is possible that other types of yet unknown phytoestrogens or components in soy other than phytoestrogen influence hot flushes.
Phytoestrogens recently gained much attention after reports that women with diets rich in those compounds had a low incidence of estrogen-related cancers,1 cardiovascular diseases,2 and climacteric symptoms.3 Phytoestrogens in the human diet include many substances classifiable as lignans, isoflavones, and coumestrans, some of which are still unidentified. Intestinal flora strongly affects conversion of inactive plant precursors in active compounds. That process has very high interindividual and intraindividual variation and is influenced by many factors such as use of antibiotics. We have not yet identified the phytoestrogen or the combination of phytoestrogens that has optimal clinical and disease prevention effects.
To study the possible mechanisms of phytoestrogen metabolism and their effects on climacteric symptoms, we investigated how a dietary soy supplement influenced phytoestrogen levels in serum and urine, and how those correlated with clinical effects on hot flushes and vaginal maturation indices in Italian women.
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Materials and Methods |
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All subjects gave written informed consent and the University of Ferrara Ethics Committee approved the study. After the run-in period, women were randomly assigned to daily supplements of 60 g of soy powder, (Supro Brand; Protein Technologies, St. Louis, MO) or 60 g of casein (placebo). The women were first seen at screening visits, then at 4-week intervals during treatment. Subjects recorded their hot flushes daily in a diary. Lateral vaginal wall cytology was checked before randomization and at the end of the trial. Vaginal maturation indices were calculated with the Hustin and Van den Eynde formula.4 Blood was collected at screening visits and at the end of the trial, whereas random urine samples were collected at any one of the visits during treatment.
The phytoestrogens, enterolactone, genistin, daidzin, and equol, were measured in blood and urine. Blood samples were collected after overnight fasts, then were centrifuged and the serum collected. Urine and serum samples were frozen and sent on dry ice to the Mass Spectrometry Unit of The Tenovous Cancer Research Centre in Cardiff, UK at the end of the trial. Serum and urinary phytoestrogen concentrations were measured by isotope dilution gas chromatography-mass spectrometry, as described previously.5
Data are given as mean ± standard error of the mean or range. The Spearman rank correlation analysis was used to correlate phytoestrogen levels in serum and urine, and serum phytoestrogen levels with the decrease of hot flushes. Nonparametric tests such as Kruskal-Wallis, and parametric tests such as Student t test, were used as needed. Two-tailed P 
.05 was considered statistically significant.
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Results |
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). Forty women in the soy group and 39 in the casein group completed the 12-week study. Blood for phytoestrogen determination was available only in 36 subjects in the soy group and 36 in the casein group. Random urine samples were collected from 35 subjects in the soy group and 35 in the casein group.
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). Mean serum values of equol increased 1008% compared with baseline in the soy group (2.26 ng/mL before and 25.06 ng/mL after treatment). Genistin mean serum values increased by 756% and daidzin by 593%. Plasma levels of genistin and equol at 12 weeks were 10.4% and 36% lower, respectively, compared with baseline values in the control group. The differences between mean serum levels of equol, daidzin, and genistin between the soy and placebo groups at the end of treatment were highly significant (P < .01) (Table 1). Plasma enterolactone was higher in the soy group at the end of treatment by approximately 57% compared with baseline, but there was no statistically significant difference with the placebo group (Table 1).
All urinary isoflavones were significantly higher in the soy group than the control group, and the differences were statistically significant. The lignan enterolactone was not different between groups (P < .2) (Table 2). Plasma levels of the isoflavones genistin, daidzin, equol, and enterolactone correlated well with urine levels (r = 0.98, P < .01; r = 0.99, P < .01; r = 0.86, P < .01; and r = 0.98, P < .01; respectively).
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Vaginal maturation indices did not increase in the soy group but were statistically significantly increased in the casein group (P < .05 with paired Student t test).
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Discussion |
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and 2). High concentrations of isoflavones also are found in urine of Japanese women who eat a traditional diet containing many soy products.6 Soy supplementation did not alter vaginal maturation indices, but there was a change in the casein group, which is not easily explained other than as a chance finding. However, casein is a protein derived from cow milk, which has been identified as a source of equol and enterolactone.7 The effects of dietary supplementation with phytoestrogen-rich food on vaginal maturation indices has produced contradictory results8,9 that might be explained by an incomplete estrogenic action of phytoestrogens on estrogen-responsive cells, depending on age, prevailing endogenous estrogens, and diet.10
Soybeans contain high amounts of genistin, daidzin, and glycitin, which become biologically active only after removal of the sugar moiety by gut microflora. The influence of small modifications of diet or intestinal flora on isoflavone metabolism and excretion might explain the great interindividual variation between phytoestrogen levels that was observed in our subjects and in the Asian population.11 This large interindividual and intraindividual variation might also explain why we found no correlation between serum levels of the phytoestrogens and clinical effects on hot flushes. There are many other possible explanations for that phenomenon, and further studies are needed to find the effective compound in soy and its minimal effective dose. So far only soy-supplemented diets have proved to be clinically effective, whereas isolated phytoestrogen tablets, such as those derived from red clover that have been used for relief of hot flushes ( Eden JA, Knight DC, Hoves JB, Mackey R. A controlled trial of isoflavones for menopausal symptoms. 8th International Congress on the Menopause. Abstract Book. Sydney 1996:115) or to lower cholesterol levels12 have not been clinically useful.
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Footnotes |
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Received November 3, 1998. Received in revised form January 21, 1999. Accepted February 10, 1999.
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References |
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2. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effect of soy-protein intake on serum lipids. N Engl J Med 1995;333:276–82.
3. Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of soy supplementation on hot flushes. Obstet Gynecol 1998;91:6–11.[Abstract]
4. Hustin JP, Van den Eynde JP. Cytologic evaluation of the effects of various estrogens given in menopause. Acta Cytol 1977;21:225–8.[Medline]
5. Morton MS, Matos-Ferreira A, Abranches-Monteiro L, Correia R, Blacklock N, Chan PS, et al. Measurement and metabolism of isoflavonoids and lignans in the human male. Cancer Lett 1997; 114:145–51.[Medline]
6. Adlercreutz H, Honjo H, Higashi A, Fotsis T, Hamalainen E, Hasegawa T, et al. Urinary excretion of lignans and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional Japanese diet. Am J Clin Nutr 1991;54:1093–2000.
7. Bannwart C, Adlercreutz H, Fotsis T, Wahala K, Hase T, Brunow G. Identification of isoflavonic phytoestrogens and of lignans in human urine and in cow milk by GC/MS. In: Todd JFJ, ed. Advances in mass spectrometry–85. Chichester: John Wiley, 1986:661–2.
8. Wilcox G, Wahlqvist ML, Burger H, Medley G. Oestrogenic effects of plant foods in postmenopausal women. BMJ 1990;301:905–6.
9. Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell KD, Weinberg CR, et al. Dietary intervention study to assess the estrogenicity of dietary soy among postmenopausal women. J Clin Endocrinol Metab 1995;80:1685–90.
10. Adams NR. Organisational and activational effects of phytoestrogens on the reproductive tract of ewe. Proc Soc Exp Biol Med 1995;208:87–91.[Abstract]
11. Adlercreutz H, Markannen H, Watanabe S. Plasma concentrations of phytoestrogens in Japanese men. Lancet 1993;342:1209–10.[Medline]
12. Hodgson JM, Puddley IB, Beilin LJ, Mori TA, Croft KD. Supplementation with isoflavonoid phytoestrogens does not alter serum lipid concentrations: A randomized controlled trial in humans. J Nutr 1998;128:728–32.
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