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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5180-5185
Copyright © 2003 by The Endocrine Society

Evidence of a Lack of Effect of a Phytoestrogen Regimen on the Levels of C-Reactive Protein, E-Selectin, and Nitrate in Postmenopausal Women

E. Nikander, M. Metsä-Heikkilä, A. Tiitinen and O. Ylikorkala

Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Eini Nikander, 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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Phytoestrogens are thought to be beneficial to vascular health. Possible mechanisms of action could involve C-reactive protein (CRP), endothelial E-selectin, and nitric oxide. We therefore designed a randomized, placebo-controlled, double-blind trial in which we studied the effects of isoflavonoids on CRP, E-selectin, and nitrate-nitrite (NOx; reflecting the release of nitric oxide) in postmenopausal women. Fifty-six postmenopausal women (FSH > 30 U/liter) with a history of breast cancer used (in a randomized order) phytoestrogen (114 mg isoflavonoids) or placebo tablets daily for 3 months; the treatment regimens were crossed over after a 2-month washout period. The serum levels of CRP and E-selectin, and plasma levels of NOx were measured before and on the last day of each treatment. The phytoestrogen regimen did not affect the levels of either CRP (P = 0.584) or NOx (P = 0.270), but the levels of E-selectin were reduced by 4.0% (2.9 ng/ml; P = 0.031) during phytoestrogen use and by 2.2% (1.3 ng/ml; P = 0.023) during placebo use. No difference was found at any marker at 3 months between the groups. In conclusion, our data, suggesting neutral effects of phytoestrogens on CRP, E-selectin, and nitric oxide, fail to support a vasoprotective role of phytoestrogens.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PHYTOESTROGENS, PRESENT abundantly in soybeans and red clover, are constituted mainly of isoflavones, such as genistein and daidzein (1). Phytoestrogens are widely used by postmenopausal women for the treatment of menopausal complaints, although scientific evidence of their benefits or hazards is often insufficient (2, 3, 4). However, the results of some observational studies suggest a vascular benefit of phytoestrogens (5, 6), and this may be supported by the binding of genistein and daidzein to estrogen ß-receptors in vascular walls (7, 8, 9). Phytoestrogens also induce small or no changes in lipids and lipoproteins (10, 11). A vascular benefit of phytoestrogens is also supported by data from ovariectomized monkeys, whose lipids were reduced and atherosclerosis delayed while they were treated with phytoestrogens (12). However, more data on the effects of phytoestrogens on atherosclerosis in humans are needed (13). Another mechanism of phytoestrogen action could involve endothelial release of nitric oxide (NO), which maintains vascular health by causing vasodilatation and antiaggregation of platelets (14). Controversial data exist on the effect of phytoestrogens on endothelial cell function. Genistein has been proven to stimulate the release of NO in some animal experiments (15, 16) and also in postmenopausal women (17), but, on the other hand, no change in endothelial function was seen after genistein supplementation at 80 mg/d in postmenopausal women (18).

It has become established that the levels of C-reactive protein (CRP), as detected by highly sensitive assays, can be elevated in individuals at increased risk of myocardial infarction (19, 20, 21). This has led to the theory that atherosclerotic diseases in coronary and other arteries can be a reflection of inflammation, which, in turn, through the release of cytokines, leads to increased synthesis of CRP in the liver (22). However, it is possible that CRP itself can act as a promoter of atherosclerotic diseases (23, 24, 25, 26, 27). Therefore, it is of interest that various forms of oral estrogen plus progestin replacement therapy (HRT) have been associated with moderate elevations in CRP levels from baseline in many (28, 29, 30), although not in all (31), studies. However, CRP levels remain generally within normal limits also during oral HRT (28, 29, 30). No data exist on the effect of phytoestrogens on CRP, except for one study in which a 1-month course of phytoestrogen caused no change in CRP concentrations (32).

Endothelial adhesion molecules, of which E-selectin is one of the most established, facilitate the recruitment of leukocytes from the bloodstream to activated endothelium (33, 34). Plasma levels of E-selectin may serve as a marker of atherosclerosis and a predictor of coronary heart disease (35). Nothing is known about the effect of phytoestrogens on E-selectin, but an abundance of data has shown that different forms of HRT result in decreased circulating levels of E-selectin (28, 31, 36, 37). In addition to adhesion molecules, endothelial NO can be a factor involved in HRT use, and indeed, NO production is reduced in postmenopausal women (38, 39) but is stimulated by HRT (38, 40).

Postmenopausal women surviving breast cancer are often advised against the use of HRT, and as a consequence they seek relief from their hot flashes and other climacteric symptoms by using phytoestrogens. This allowed us to design a placebo-controlled crossover trial in such women to assess the effects of phytoestrogens on vascular surrogate markers: CRP, E-selectin, and plasma NO.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and study design

With permission from the local ethics committee, we studied postmenopausal women who had been treated for breast cancer more than 6 months previously (Table 1Go). The volunteers received thorough written and verbal information on the purpose and procedures of the study, and an informed consent was obtained from all of them. Thirteen women (11 premenopausal and 2 postmenopausal) had received chemotherapy at a mean of 5 yr before recruitment. Three patients had used tamoxifen for 2 months to 4 yr, but this treatment had been discontinued 5 months to 4 yr before recruitment. Each woman was devoid of any metastasis at recruitment, which took place between September 1, 1999, and October, 10, 2000. All women had incapacitating hot flashes and other climacteric symptoms; menopausal status was confirmed by serum FSH exceeding 30 U/liter. The women were not using HRT, statins, natural products with presumed estrogenic activity, or drugs possibly affecting climacteric symptoms or metabolism and absorption of phytoestrogens (e.g. antibiotics during the previous 3 months). None had a history of a thromboembolic or a hepatic event. Before the diagnosis of breast cancer, 22 of the 56 women who completed the trial (39.3%) had used some form of HRT. Eight women took antihypertensive drugs.


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  		TABLE 1. Clinical characteristics of the study population (n = 56)

 
Following a double-blind, crossover technique, the women were treated in computer-randomized order either with phytoestrogen or a similar-looking placebo. Each treatment lasted 3 months, and the treatment phases were interrupted by 2-month washout periods. Before starting this trial we carried out a pilot study on 54 healthy postmenopausal women to determine the adequate dose of phytoestrogens. Daily administration of 58 mg isoflavones (Bonette, Novomed, Helsinki, Finland) resulted in 20- to 35-fold increases in the circulating levels of phytoestrogens, with moderate interindividual variations. As this dose was well tolerated, we decided to further increase the dose to 114 mg in the present study to guarantee adequate dosage (41). Three phytoestrogen tablets or 3 similar-looking placebo tablets were to be taken every 12 h with a glass of water (6 tablets/d). Each phytoestrogen tablet consisted of glycitein (11 mg, 58%), daidzein (7 mg, 37%), and genistein (1 mg, 5%).

The women visited the research center before and after each treatment period. General and pelvic examinations were performed, and appropriate blood and other samples were collected. 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 the use of antibiotics or other concomitant drugs. Compliance with the use of the study medication was confirmed by checking diaries and analyzing serum levels of the phytoestrogens daidzein and genistein, as reported previously (41).

Laboratory methods

The use of food rich in nitrate (red meat, sausages, red beet, and spinach) was not allowed for 48 h before blood sampling, which took place after an overnight fast immediately before the start of the regimen and on the last day of each treatment period. Serum and plasma were separated by centrifugation and kept frozen at -20 C until assayed. Serum CRP was measured immunochemically using monoclonal antibodies produced in mice (DADE-Behring GmbH, Marburg, Germany). The detection limit was 0.085 mg/liter. Coefficients of intra- and interassay variation were between 2 and 4%. Serum E-selectin concentrations were measured using a sandwich enzyme immunoassay (R&D Systems, Minneapolis, MN). The coefficient of intraassay variation was less than 5%, and that of interassay variation was less than 9%. Plasma NO was oxidized to nitrite and nitrate (NOx), which was then assayed by means of the Griess reaction and spectrophotometry, as described previously (42, 43). The coefficients of intra- and interassay variation of the NOx assay were 3% and 11%, respectively. Serum concentrations of FSH and estradiol were measured by means of solid phase fluoroimmunometric assays (Delfia, Wallac Oy, Turku, Finland). The coefficients of intraassay variation were 3% for FSH and 10% for estradiol, and those of interassay variation were less than 2% and 10%, respectively.

Statistical analyses

The data, presented as the mean ± SD, were analyzed using the SPSS 10.0 statistical package (SPSS Institute, Inc., Chicago, IL). Nonparametric (sign) tests were used to determine any changes (difference between baseline and posttreatment values) in CRP, E-selectin, and NOx. These tests were also used to compare the effects of phytoestrogen and placebo treatment. At baseline, Spearman rank correlations for nonparametric data were used to investigate the relationships between the variables in each of the treatment groups. The levels at baseline were compared using Mann-Whitney U tests. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of 64 women screened, 62 could be randomized. Two women were excluded, 1 because her FSH level was less than 30 U/liter, and the other because she had taken a course of antibiotics within the previous 3 months. Thirty-two women were to start with phytoestrogens, and 30 with placebo. Six women discontinued the trial during the first treatment regimen: 4 in the phytoestrogen group (2 because of stomach ache, 1 for personal reasons, and 1 because of recurrent breast cancer) and 2 in the placebo group (1 because of lack of effect and 1 because of vaginal bleeding). The fifty-six women completing the trial reported no relief of vasomotor symptoms after taking phytoestrogens. Phytoestrogens had no effect on either systolic or diastolic blood pressure or levels of FSH and estradiol.

The use of phytoestrogens led to significant rises in the levels of daidzein (a rise of 1059.6 ± 782.5 nmol/liter) and genistein (403.8 ± 275.7 nmol/liter; 20-fold rise), whereas the placebo regimen had no effect.

All data were first analyzed separately for the first and second treatment phases, and because the order of treatment was not a confounding factor, the data were pooled to form a single phytoestrogen and a single placebo group. Six women exhibited 14 CRP values over 5 mg/liter, and these values were excluded from the final analysis.

Age, years since menopause, previous use of HRT, and history of hysterectomy or hypertension were not determinants of basal levels of CRP, E-selectin, or NOx (Table 2Go). However, CRP levels showed positive relationships with body mass index (Spearman’s correlation coefficient = 0.501; P = 0.0002) and E-selectin concentrations (Spearman’s correlation coefficient = 0.316; P = 0.023). CRP and E-selectin were not correlated with NOx. Smoking was associated with elevated CRP, but normal E-selectin and NOx levels (Table 2Go). Individual changes in CRP, E-selectin, and NOx showed no dependence on each other or on any clinical variable (age, postmenopausal period, or body mass index; data not shown).


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  		TABLE 2. Basal levels of circulating CRP, E-selectin, and NOx in relation to clinical variables (<= or > median) in postmenopausal women starting the phytoestrogen or placebo regimen (n = 56)

 
The phytoestrogen regimen did not affect the levels of CRP and NOx when analyzed with regard to changes from basal levels or changes in the placebo group (Table 3Go). However, it was associated with a reduction in the levels of E-selectin (4.0% drop; P = 0.031) from baseline to 3 months. However, the placebo regimen was also associated with a decline (2.2% drop; P = 0.023) in E-selectin levels. Thus, E-selectin concentrations at 3 months did not differ between phytoestrogen and placebo groups (P = 0.894; Table 3Go). When E-selectin levels at 0 and 5 months were compared, a P value of 0.073 suggested that there might be some carryover effect.


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  		TABLE 3. Levels of CRP, E-selectin, and NOx before and at the end of phytoestrogen and placebo treatment for 3 months (n = 56)

 
Increases in daidzein and genistein levels were in a direct relation to reductions in E-selectin levels (Spearman’s correlation coefficient = 0.391; P = 0.003 and Spearman’s correlation coefficient = 0.382; P = 0.004, respectively), but not with changes in CRP or NOx (Table 4Go).


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  		TABLE 4. Absolute changes in the levels of phytoestrogens, CRP, E-selectin, and NOx

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We studied the effects of phytoestrogens on the vascular surrogate markers CRP, E-selectin, and NOx in postmenopausal women who had had breast cancer. Eleven women had received chemotherapy while they still were premenopausal, and this may have prompted the onset of menopause in these individuals. In addition, three subjects had used tamoxifen, but because this treatment had been discontinued well before our trial, tamoxifen was not a cause of the vasomotor symptoms in our patients. Thus, we believe that our patients suffered primarily from similar climacteric symptoms as healthy postmenopausal women. It is further unlikely that a history of breast cancer without any concomitant use of chemotherapy or tamoxifen could modify endothelial function. Therefore, we feel that our study group is, rather, representative of healthy postmenopausal women, although they had a history of breast cancer. A 2-wk soy supplementation had a weak estrogenic effect on normal premenopausal breast (44), and phytoestrogen may also exert nongenomic effects on breast cancer cells (45). All of this implies that longer-term supplementation studies are needed to determine the safety of phytoestrogens on healthy and/or cancerous breast tissue, although we did not observe any breast tenderness or other subjective breast side effects in our study, which lasted 3 months. We carefully determined the adequate dose of phytoestrogen in our pilot study (41) to be sure that our regimen could really raise the circulating levels of phytoestrogens; similar doses of phytoestrogens have also been used by others (46, 47). We administered phytoestrogen for 3 months, because it is known that various forms of HRT modify the levels of vascular markers within 4–6 wk (48, 49). Therefore, we believe that the 3-month exposure to phytoestrogens was long enough to reveal a possible effect. However, in view of the large biological variation in these markers, it is possible that our study was underpowered to detect some effects, if they exist.

Although our phytoestrogen regimen led to consistent and large increases in the circulating levels of isoflavonoids (41), it failed to affect the levels of CRP. CRP is primarily derived from the liver, and therefore it was of significance that phytoestrogen did not affect the levels of liver enzymes in our patients (41). We may now conclude that phytoestrogens do not have any direct or indirect effect on the synthesis of CRP in the liver. However, a smaller proportion of CRP may come directly from vascular walls (21), and our data, suggesting unaltered CRP levels during phytoestrogen use, can be seen as evidence that phytoestrogens do not affect any extrahepatic production of CRP either. This is an important piece of information, because CRP per se may contribute to vascular pathology by inducing the expression of adhesion molecules, such as E-selectin, by activating complement pathways, increasing low density lipoprotein uptake, stimulating monocyte chemotaxis, and inhibiting neutrophil chemotaxis or NO function in endothelial cells (23, 24, 25, 26, 27). If these mechanisms of action of CRP truly operate in vivo in apparently healthy women, oral phytoestrogens that leave CRP unaffected appear neutral for vascular health. Our data are also of significance for epidemiologists searching for explanations for variations in CRP levels; phytoestrogens are not likely to be a cause. Moreover, our data are in line with previous findings that a 1-month, high isoflavone regimen (73 mg/d) caused no changes in levels of CRP, serum amyloid A, or TNF{alpha} in middle-aged men and women (32). Our findings expand this information in that no effect of phytoestrogens on CRP is apparent even after 3-month use in postmenopausal women. Thus, our data and those of others (32) imply that phytoestrogens are neutral toward CRP and perhaps also with regard to those vascular disorders in which CRP plays a role. It was conspicuous, however, that in our study obesity and smoking were associated with higher levels of CRP, as in some previous studies (50, 51).

E-Selectin and NO are both products of endothelial cells, and in principle, a low level of E-selectin and a high level of NO should be beneficial for vascular health. We assessed NO release by measuring plasma NOx, which is subject to large variation and potential error via dietary NOx, although this source of error was eliminated as far as possible in a clinical study. Phytoestrogens failed to affect plasma NOx levels, unlike in a previous study (17). This may reflect a real lack of effect of phytoestrogens on NO synthesis in our subjects or insensitivity of the NOx assay to detect small changes in NO release, which could be physiologically significant. An invasive endothelial test, requiring intraarterial injection of acetylcholine and consequent release of NO, could be more representative. Dietary isoflavones have been shown to enhance NO release in female monkeys (15) and, more interestingly, in healthy middle-aged men and women (52).

Serum concentrations of E-selectin fell by 4.0% (P = 0.031) during the phytoestrogen regimen, but they were also reduced during the placebo regimen, although to a lesser degree; this is probably the result of normal biological variation. The greater reductions in E-selectin concentrations in women with higher daidzein and genistein levels may suggest that phytoestrogens can reduce the levels of E-selectin, at least at high concentrations, as suggested by the correlation between reductions in E-selectin levels and elevations in levels of phytoestrogens in our study. This reduction, if proved to be true in a larger study, is in theory vasoprotective (35, 53). In this regard, phytoestrogens may resemble HRT regimens, which are known to reduce the levels of E-selectin by 18–35% (28, 31, 37). This possible endothelial effect of phytoestrogens could be product-specific, as the levels of NOx did not change.

In summary, the use of isoflavonoids by postmenopausal women failed to affect the concentrations of the vascular surrogate markers CRP and NOx, but a trend toward reduced E-selectin levels was seen. These data suggest a neutral effect of phytoestrogens on vascular physiology, at least in women who have been treated for breast cancer.


   Footnotes
 
This work was supported by grants from the research funds of the Helsinki University Central Hospital and the Juho Vainio Foundation.

Abbreviations: CRP, C-Reactive protein; HRT, estrogen plus progestin replacement therapy; NO, nitric oxide; NOx, nitrate-nitrite.

Received February 28, 2003.

Accepted July 15, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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