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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital; National Public Health Institute; and Division of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
Address reprint requests to: Eini Nikander, MD, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HUS, Helsinki, Finland; E-mail: eini.nikander{at}pp.fimnet.fi.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Sixty-two postmenopausal symptomatic women were randomized to use either phytoestrogen (tablets containing 114 mg of isoflavonoids) or a placebo for 3 months; the treatment regimens were reversed after a 2-month washout period. Fifty-six women completed the study. Menopausal symptoms were recorded on the Kupperman index and the visual analogue scale, and working capacity and mood changes were assessed via validated questionnaires. In addition, we followed the levels of phytoestrogens, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and sex hormone–binding globulin. Liver enzymes and creatinine were also assessed at each visit.
RESULTS: The phytoestrogen regimen raised the circulating levels of phytoestrogens (daidzein, genistein, equol) 19- to 106-fold. The Kupperman index was reduced by 4.2 ± 9.6 (mean ± standard deviation) (15.5%) during phytoestrogen use and similarly by 4.0 ± 8.1 (14.7%) during placebo use (P nonsignificant). The quality of life parameters (working capacity, mood changes) were unaffected by phytoestrogen. In addition, the phytoestrogen regimen caused no changes in FSH, LH, estradiol, or sex hormone-binding globulin. Phytoestrogen treatment was well tolerated and caused no changes in liver enzymes, creatinine, body mass index, or blood pressure. Of the 56 women, 25 (44.6%) preferred the phytoestrogen regimen, 15 preferred the placebo (26.8%), and 16 (28.6%) reported no preference (nonsignificant).
CONCLUSION: Pure isoflavonoids did not alleviate subjective menopausal symptoms in breast cancer patients.
Phytoestrogens, present in a number of edible plants (eg, soybeans and red clover), mainly comprise isoflavones such as genistein and daidzein.1 Various studies carried out in vitro and animal experiments have shown that phytoestrogens bind weakly to the estrogen 
-receptor and more strongly to the estrogen ß-receptor and that they may possess organ-specific estrogenic and antiestrogenic effects.2,3 Phytoestrogens are popular among the public in the treatment of menopausal symptoms,4,5 although hardly any scientific evidence exists for their efficacy.6,7
Previous data on the effects of isoflavonoids on postmenopausal hot flashes are controversial because some authors have reported a significant reduction in their occurrence during daily intake of soy protein (containing 76 mg8 or 100 mg9 of isoflavonoids), whereas others have noted no specific effects of soy flour,10 isoflavonoids (40 mg daily),11 or isoflavone-rich or isoflavone-poor soy protein.12 The circulating levels of sex hormone–binding globulin and follicle-stimulating hormone (FSH) have been reported not to be affected by 40–160 mg of isoflavones daily,11,13,14 whereas in one study both isoflavonoids and a placebo regimen reduced the level of FSH.9
Randomization of symptomatic postmenopausal women to a placebo regimen or to a regimen the effect of which is unknown (such as phytoestrogen) may present an ethical dilemma because hormone replacement therapy (HRT) alleviates climacteric symptoms rapidly and effectively. Studying women with treated breast cancer may overcome this dilemma because these women are usually denied HRT.15,16 Breast cancer survivors have therefore volunteered in some phytoestrogen studies, but 150 mg17 or 90 mg18 of isoflavonoids for 4–12 weeks failed to relieve their hot flashes. In these trials, 78%17 and 31%18 of patients suffered from tamoxifen-induced hot flashes that may differ in mechanism and treatment response from those associated with natural menopause. In addition to hot flashes induced by antiestrogens, breast cancer survivors may also suffer from estrogen deficiency–induced menopausal symptoms.19 We therefore recruited a representative group of breast cancer survivors (none using tamoxifen) who complained of incapacitating hot flashes and other climacteric symptoms after the onset of spontaneous menopause, as seen from their high circulating levels of FSH and luteinizing hormone (LH). They took part in a placebo-controlled double-blind crossover trial with phytoestrogen and a placebo. Our study was designed to evaluate changes relative to the placebo in postmenopausal symptoms and quality of life in response to 3 months’ use of 114 mg of isoflavonoids per day.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Before starting the crossover trial we carried out a pilot study on 54 healthy postmenopausal women with and without hot flashes to determine the dose of phytoestrogens sufficient to raise their levels in blood (Kilkkinen A, Valsta LM, Nikander E, Tiitinen A, Adlercreutz H, Tikkanen MJ, et al. Serum phytoestrogens after consumption of phytoestrogen products: A randomized trial in middle-aged women. Poster presented at the Fourth International Conference on Dietary Assessment Methods; September 17–20, 2000; Tucson, Arizona). Daily administration of 58 mg of isoflavones (Bonette; Novomed, Helsinki, Finland) resulted in 20–35-fold rises in the circulating levels of phytoestrogens, with moderate interindividual variations. As this dose was well tolerated, we decided to give 114 mg of phytoestrogens in the present study to guarantee adequate dosage; this consisted of glycitein (58%), daidzein (36%), and genistein (6%).
After use of a double-blind crossover technique, the women were treated in computer-randomized order with either phytoestrogen or a similar-looking placebo. Each treatment lasted 3 months, and the treatment phases were interrupted by 2-month washout periods. Phytoestrogen tablets and similar-looking placebo tablets (six tablets per day) were to be taken every 12 hours with a glass of water.
The patients were seen at the research center before and after each treatment period. General and pelvic examinations were performed and appropriate blood and other samples collected. At each visit the patients were carefully interviewed about hot flashes and other typical climacteric symptoms (Kupperman index). In addition, we determined the total severity of the menopausal syndrome with the aid of a 10-cm-long visual analogue scale. The women were also asked to rate their physical and mental working capacity in a previously established diary employing five specific questions, on a scale from very poor (1) to very good (5). In addition, they rated their present overall work capacity relative to their lifetime best on a scale of 0–10. The scores from these six questions were balanced and summed and used as the Work Ability Index, as described elsewhere.20 A score of 3–13 indicated poor working capacity, 14–17 moderate, 18–21 good, and 22–24 excellent. Depressive mood, anxiety, and the level of self-confidence were recorded by use of established indexes.21 Depression was assessed by means of 13 questions concerning mood, social behavior, and opinion of the future. Each answer was rated on a scale of 0 (positive) to 3 (negative). A sum of 5–7 was judged to indicate mild depression; between 8 and 15, moderate depression; and over 16, severe depression. Anxiety and self-confidence were separately determined by means of specific questions.21
During the study the women were encouraged to lead normal lives with no changes in dietary habits, alcohol consumption, or physical activity, which were all recorded by means of questionnaires before and at the end of each treatment period. They kept weekly diaries concerning their general health, possible side effects, bleeding, and use of antibiotics or other concomitant drugs. At the end of the last treatment period, each woman was asked to indicate her preference regarding the treatments.
Blood samples taken after an overnight fast were collected immediately before the start of the regimen and on the last day of each treatment period. Serum was separated by centrifugation and stored frozen (-20C) until assayed for daidzein, genistein, and equol using established methods.22 This was carried out to confirm compliance with the treatment. Aliquots were also assayed for FSH, LH, estradiol, and sex hormone–binding globulin using validated routine laboratory methods. To avoid interassay variation, all assessments were run in the same assay. The intraassay coefficient of variation was 2.0–2.8% for FSH, 2.0–2.4% for LH, 3.8–10.0% for estradiol, and 1.3–1.8% for sex hormone–binding globulin. In addition, serum was used to assess aspartate transaminase, alanine transaminase, and creatinine using routine laboratory methods.
The data are presented as mean ± standard deviation (SD). Paired t tests or nonparametric (sign) tests were used to determine any changes (difference between posttreatment and baseline values) in the main variables. These tests were also used to compare the effects of the two treatments, and the 
2 test was used to analyze the subjects’ preference regarding treatments. Because the levels of equol, which is exclusively produced by intestinal bacteria from precursor isoflavonoids of dietary origin, may determine the health effects of soy isoflavonoids (Setchell KDR. Equol–is it good to be a producer? [abstract]. Presented at the Soy & Health 2002 congress; May 30–31, 2002; London), we also carried out a subgroup analysis based on pretrial levels of equol (below median = "low" producers, above median = "high" producers). Statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC) and SPSS (SPSS Inc., Chicago, IL) programs. A P value of less than .05 was considered significant. A sample size of 54 women was chosen for 95% power to detect a 40% difference between treatments in the mean number of hot flashes, with an SD of 2.2. No carryover effect was detected regarding main variable measured.
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RESULTS |
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We screened 64 women; two patients were excluded, one because her FSH level was below 30 U/L and the other because she had taken a course of antibiotics less than 3 months before the study. Of the 62 women eligible for randomization, 32 were to start with phytoestrogens and 30 with the placebo (Figure 1
). Because these groups were comparable in relevant clinical variables and levels of FSH, LH, estradiol, and sex hormone–binding globulin, in data analysis no difference was made according to order of regimens. Six women discontinued the trial for various reasons during the first phase, leaving 56 women who completed it (Figure 1 and Table 1).
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).
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). The phytoestrogen regimen reduced the Kupperman index by 4.2 ± 9.6 (15.5%) (P = .002), but this reduction did not differ from that during the placebo regimen (4.0 ± 8.1, 14.7%). Thus, Kupperman indexes at the end of phytoestrogen or placebo treatment did not differ (Table 2). Neither hot flashes nor any other components of the Kupperman index were relieved by the phytoestrogen regimen when evaluated separately. The total severity of menopausal symptoms on the visual analogue scale ranged from 8 to 89 mm before the trial (55.7 ± 20.0), from 1 to 100 mm (46.5 ± 26.5) after phytoestrogen, and from 3 to 100 mm (49.3 ± 23.1) after the placebo regimen (P = .469, nonsignificant).
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). The data were also analyzed as to baseline equol levels (low equol producers, n = 28, 1.41 ± 0.42 nmol/L; high equol producers, n = 28, 4.22 ± 4.42 nmol/L). The basal equol level was not a determinant of the effect of phytoestrogens on any of the variables mentioned above (data not shown). Twenty-five women (44.6%) preferred the phytoestrogen regimen, and 15 (26.8%) the placebo (nonsignificant), whereas 16 (28.6%) had no preference for either treatment.
Both the phytoestrogen and the placebo regimen failed to affect levels of FSH, LH, estradiol, or sex hormone–binding globulin (Table 3), and neither was this finding affected by the pretrial level of equol, nor did any changes appear in aspartate transaminase, alanine transaminase, creatinine, blood pressure, or body mass index.
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DISCUSSION |
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Advocates of phytoestrogens may criticize our study because of the short duration (3 months) of the study period. This is unlikely because the levels of phytoestrogens would have been constantly elevated from 6 to 8 hours after the start of the trial.23 Moreover, HRT alleviates hot flashes within the first few days of initiation.24 However, it is possible that phytoestrogens may trigger changes in target organs in processes requiring more than 3 months. Thus, long-term data on the effects of phytoestrogens would be valuable. Second, it can be asked whether the doses were physiologically suitable.The doses appeared large enough, given the elevations in the levels of phytoestrogens in the subjects. Importantly, these elevations were of the same order of magnitude as those reported by other investigators using different treatment modalities.25,26 Third, our phytoestrogen regimen contained mainly glycitein, whose effects on menopausal complaints have not been previously explored. However, we also gave daidzein (41 mg) and genistein (6.8 mg) at doses similar to those used before.19,27 Thus, the dosage of phytoestrogen in our trial was neither unphysiologic nor too small. It remains open whether the dosage was too large and the circulating levels of phytoestrogens too high. Perhaps under these conditions phytoestrogens do not behave as estrogens but rather as antiestrogens. This criticism is unlikely because the serum levels of FSH and sex hormone–binding globulin, which react relatively sensitively to both estrogenic and antiestrogenic compounds,28–30 did not change. Fourth, one could argue that good producers of endogenous equol would not benefit from additional isoflavonoids,15 and that our volunteers were all "good" equol producers. There is no normal range for equol levels, and therefore we analyzed our data separately in a low equol group (below the median) and a high equol group (above the median). However, phytoestrogens were equally ineffective in both groups, suggesting that endogenous equol did not blunt the possible effects of phytoestrogens. We are therefore rather confident that the isolated isoflavonoids used in our trial did not relieve menopausal complaints. It is a different question whether isoflavonoids, if administered concomitantly with soy protein, would be more effective, perhaps because of the action of soy protein itself.31
One additional confounding factor may be the levels of endogenous estrogens, which may perhaps modify the responses to phytoestrogens. Phytoestrogens may require some estrogens to become effective, and our subjects were perhaps too hypoestrogenic. These factors may, in part, account for the variability in previous data on the effects of phytoestrogens on menopausal complaints. In various studies comparing phytoestrogens with a placebo in alleviating climacteric symptoms, a placebo effect has been reported to be 18–30%,16,18,19 whereas in only one study was there no placebo effect at all.17 Although this was the case, there was a similar decrease in FSH levels in both the phytoestrogen and the placebo groups, with estradiol increasing only in the phytoestrogen group.17 In our trial the Kupperman index and separate index for hot flashes were reduced by 15% after both the phytoestrogen and the placebo treatment periods, with no changes in gonadotropin or estradiol levels.
Phytoestrogens are known to bind to both estrogen -receptor and estrogen ß-receptor.2 This binding can be so tissue-specific that even though no changes in hot flashes or FSH, LH, estradiol, or sex hormone–binding globulin levels were evident in our subjects, the possibility exists that ß-receptors located in vascular walls and bone cells2,32 were stimulated by the phytoestrogens employed in our study. It is therefore worthwhile studying markers reflecting vascular physiology or bone metabolism in our volunteers to see whether our regimen indeed affected vascular or bone physiology.
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Footnotes |
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doi:10.1016/S0029-7844(03)00232-1
Received August 6, 2002. Received in revised form November 26, 2002. Accepted December 4, 2002.
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REFERENCES |
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