Tea and circulating estrogen levels in postmenopausal Chinese women in Singapore

Anna H. Wu 1, *, Kazuko Arakawa 1, Frank Z. Stanczyk 2, David Van Den Berg 3, Woon-Puay Koh 4 and Mimi C. Yu 1

1 Department of Preventive Medicine, 2 Department of Obstetrics and Gynecology and 3 Department of Urology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA and 4 Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore 117597

* To whom correspondence and reprints should be addressed at: USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9175, USA. Tel: +323 865 0480; Fax: +323 865 0139; E-mail: annawu{at}usc.edu


    Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The role of tea in the etiology of breast cancer is controversial. We recently provided the first set of human evidence that breast cancer risk is significantly inversely associated with tea intake, largely confined to intake of green tea. Since black tea and green tea possess comparable levels of the total tea polyphenols that possess antioxidative activities, reasons for the paradoxical effects of green tea and black tea on breast cancer protection are not apparent. Some limited evidence suggests that green tea may have downregulatory effects on circulating sex-steroid hormones, whereas black tea may have upregulatory effects. We therefore, investigated the relationship between tea intake, and plasma estrogen and androstenedione levels in a cross-sectional study of healthy postmenopausal Chinese women in Singapore. In this group of 130 women, 84 were non or irregular (less than once a week) tea drinkers, 27 were regular (weekly/daily) green tea drinkers and 19 were regular (weekly/daily) black tea drinkers. Relative to plasma estrone levels in non- or irregular tea drinkers (29.5 pg/ml) the levels were 13% lower in regular green tea drinkers (25.8 pg/ml) and 19% higher in regular black tea drinkers (35.0 pg/ml). These differences in estrone levels were statistically significant (P = 0.03) inspite of adjusting for age, body mass index, intake of soy, and other covariates. A similar pattern of differences between tea intake, and plasma levels of estradiol (P = 0.08) and androstenedione (P = 0.14) were found. In addition, the tea–estrogen associations were observed irrespective of the genotype of catechol-O-methyltransferase (COMT), a major enzyme that aids in the excretion of tea polyphenols in humans. Larger studies are needed to confirm results from this cross-sectional study and to better understand the potentially differing effect of black and green tea on circulating estrogen levels and ultimately on the risk of breast cancer.

Abbreviations: COMT, catechol-O-methyltransferase; EGCG, epigallocatechin-3-gallate


    Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In our studies of breast cancer in Asian women, we have identified two components of the Asian diet, namely, tea and soy, to be significantly inversely associated with breast cancer risk (1,2). Specifically, in our initial study, risk of breast cancer was reduced among green tea drinkers but not among black tea drinkers (2). Methylation is a major elimination pathway for tea polyphenols (3). Interestingly, when we considered catechol-O-methyltransferase (COMT) genotype as a measure of an individual's ability to eliminate tea polyphenols, we found that tea protects against breast cancer among carriers of the low activity COMT allele but not among those who possessed two high activity COMT alleles (4). In addition, among individuals who possessed the low activity COMT allele, both green tea and black tea exhibited comparable potencies in breast cancer risk reduction (4). In our continuing efforts to better understand the relationship between tea intake and breast cancer risk, we conducted this analysis using a cross-sectional study that was designed to identify dietary and non-dietary determinants of blood hormone levels among postmenopausal Chinese women in Singapore (5). In our initial report from this cross-sectional study, we found that high body mass index (weight/height2), early age at menarche nulliparity/late age at first birth and low intake of soy were independently associated with high blood estrogen levels, whereas smoking habits and dietary factors including intake of total fat, total fiber, legumes (from non-soy sources), alcohol, and coffee were unrelated to blood estrogen levels (5). We now report our findings on the individual effects of green tea and black tea on blood estrogen and androstenedione levels. Results from this study add to the current sparse but suggestive data that tea intake may influence blood estrogen levels and also that the type of tea (green versus black) may matter (6).


    Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study population
The subjects were participants of the Singapore Chinese Health Study, a population based prospective investigation of diet and cancer risk. From April 1993 through December 1998, 63 257 Chinese women and men aged 45–74 years enrolled in the study (only women are included in this report). The subjects were residents of government housing estates; 86% of the Singapore population lived in these facilities during the period of enrollment. At recruitment, a face-to-face interview was conducted in the subject's home by a trained interviewer using a structured questionnaire. The questionnaire included a validated dietary component in which each subject was asked to estimate his or her usual intake frequencies and portion sizes for 165 food and beverage items in the past 12 months. Specific questions were asked about usual frequency of intake (never or hardly ever, 1–3 times/month, once/week, 2–3 times/week, 4–6 times/week, once/day, 2–3 times/day, 4–5 times/day and 6 or more times/day) of coffee, black tea, green tea and alcoholic beverages (7). It also requested information on demographics, lifetime use of tobacco, menstrual and reproductive history (women only), medical history and family history of cancer.

In April 1994, one year after the initiation of the cohort study, we started the collection of blood and single-void urine specimens from a random 3% sample of study enrollees and achieved a 64% response rate in biological specimen collection (8). A 20 ml blood sample was obtained from each subject. Immediately after blood collection, the tubes were placed on ice during transport from the subjects' homes to the laboratory. One 10 ml aliquot of blood was used for the preparation of serum and another 10 ml aliquot was placed in a heparin-containing tube to obtain plasma. All specimens were then separated into their various components (plasma, serum, red blood cells and buffy coat), which were subsequently stored at –80°C until analyzed. Most blood samples were collected in the morning with no requirement that the subjects fast. However, we asked and recorded the time of each subject's last meal. The present investigation on determinants of blood hormone levels included the first 149 women who were at least 50 years of age, without any history of cancer and who had experienced a natural or a surgical menopause. We included only women without any history of cancer since lifestyle habits may change as a result of cancer diagnosis and the presence of tumor and/or cancer treatment may additionally influence blood hormone levels. We also wanted to circumvent the problem of inherent cyclic variation in estrogen levels in premenoapaual women and thus limited our analysis to women who were 50 years of age or older and were postmenopausal by self-report; their postmenopausal status was subsequently confirmed by their circulating estrogen levels (5). In addition, 19 of the 149 women were excluded from the study for the following reasons; 4 were current users of replacement hormones, 1 had data missing for estrone, estradiol and androstenedione and 14 were regular drinkers of both green and black tea. We excluded subjects who drank both types of tea regularly because we hypothesized that the two types of tea might have opposing effects on blood hormone levels; therefore, users of both types of tea would be non-informative in this study. The Institutional Review Boards at the University of Southern California and the National University of Singapore have approved this study.

Hormone measurements
Plasma aliquots from subjects under study were shipped in sealed containers on dry ice to one of us (M.C.Y) at the University of Southern California. These specimens were then delivered to the laboratory of Dr Frank Stanczyk who used radioimmunoassay, previously validated in his laboratory (9,10), to measure plasma levels of estrone, estradiol and androstenedione. Prior to quantification, the hormones were first extracted with hexane:ethyl acetate (3:2) and then separated from interfering metabolites by the use of celite column partition chromatography. The interassay coefficients of variation at three (low, medium and high) concentrations of estrone, estradiol and androstenedione were between 7 and 16% (5).

COMT H/L Genotyping methods
DNA was purified from buffy coats of peripheral blood samples using a PUREGENE Blood kit (Gentra Systems, Minneapolis, MN) or a QIAamp 96 DNA Blood Kit (Qiagen, Valencia, CA). The COMT polymorphism was previously described (11) and a genotyping assay was developed for the high activity/low activity (H/L) polymorphism using the fluorogenic 5'-nuclease assay (TaqMan Assay) (12). This assay was performed using a TaqMan PCR Core Reagent kit (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. The oligonucleotide primers for amplification of the polymorphic region of COMT were GC009for (5'-GCCATCACCCAGCGGAT-3') and GC009rev (5'-AACGGGTCAGGCATGCAC-3'). In addition, the fluorogenic oligonucleotide probes used to detect each of the alleles were GC009F (5'-GATTTCGCTGGCATGAAGGACAAG-3') labeled with 6-FAM to detect the L allele and GC009C (5'-GATTTCGCTGGCGTGAAGGACAAG-3') labeled with CY3 to detect the H allele (BioSearch Technologies, Novato, CA). PCR amplification using ~10 ng of genomic DNA was performed in a thermal cycler (MWG Biotech, High Point, NC) with an initial step at 95°C for 10 min, followed by 50 cycles at 95°C for 25 s and at 62°C for 1 min. The fluorescence profile of each well was measured in an ABI 7900HT Sequence Detection System and the results analyzed with Sequence Detection Software (Applied Biosystems). Experimental samples were compared with 12 controls to identify the 3 genotypes at each locus (H/H, H/L and L/L). Any samples that were outside the parameters defined by the controls were considered as non-informative and were retested.

Statistical analysis
We used the analysis of covariance methods to compare mean plasma levels of estrone, estradiol and androstenedione by the type of tea intake and by the type of tea in combination with soy intake and COMT genotype. Age, body mass index (weight/height2) and soy were included as covariates in all analyses that compared plasma hormone levels between the different categories of tea intake, since these variables significantly influenced estrogen levels in this study population (5). The time interval between last meal and blood drawn was also included as a covariate because the three hormones under study were higher among subjects who gave fasting samples (5). We used linear contrasts (1 degree of freedom) to test for trends by tea intake.

Associations between tea intake and plasma estrogen levels were essentially identical with or without adjustment for intake of coffee, menstrual and reproductive factors. Results shown in this report did not include coffee intake, and menstrual and reproductive factors as covariates. The distributions of the hormone levels were skewed, which were corrected to a large extent by transformation to logarithmic values. Therefore, all statistical analyses were performed on logarithmically transformed values. We hypothesized that plasma estrogen levels will be lowest among regular green tea drinkers only, intermediate among non-regular tea drinkers and highest among regular drinkers of black tea only. All P values quoted are two-tailed (2P). Calculations were performed using the SAS statistical software system (SAS Institute, Cary, NC).


    Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Analyses of estrone, estradiol and androstenedione were conducted on 130 women, with the age ranging from 50 to 77 years (mean 60.2, SD 7.1), who were postmenopausal for at least one year. Table I shows that 64.6% (n = 84) were non-regular tea drinkers (66 non-tea drinkers, 18 monthly tea drinkers) (hereafter referred to as non-tea drinkers and irregular tea drinkers), 20.8%(n = 27) were weekly or daily drinkers of green tea only (hereafter referred to as regular green tea drinkers) and 14.6% (n = 19) were weekly or daily drinkers of black tea only (hereafter referred to as regular black tea drinkers). Demographic characteristics (e.g. dialect group, education), body mass index (weight/height2), age at menarche and age at first livebirth did not differ significantly between non-tea drinkers and irregular tea drinkers, regular black tea drinkers and regular green tea drinkers. However, regular black tea drinkers were less likely to be daily coffee drinkers and more likely to be higher soy consumers (i.e. highest quartile of soy protein intake) compared to regular green tea drinkers and non-tea drinkers and irregular tea drinkers (Table I).


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Table I. Selected characteristics of participants according to tea intake

 
Relative to non-regular tea drinkers, plasma estrone levels were 19% higher (35.0 versus 29.5 pg/ml) among regular drinkers of black tea only and 13% lower (25.8 versus 29.5 pg/ml) among regular drinkers of green tea only. Differences in estrone levels by tea intake were statistically significant (P = 0.03) (Table II). Similarly, plasma estradiol levels were 10% higher (15.0 versus 13.6 pg/ml) among regular drinkers of black tea only and 8% lower (12.5 versus 13.6 pg/ml) among regular drinkers of green tea only compared with non-regular tea drinkers (P = 0.08). While levels of androstenedione were also highest in regular drinkers of black tea only and lowest in regular drinkers of green tea only, these differences were not statistically significant (P = 0.14).


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Table II. Adjusteda geometric mean circulating levels of estrone, estradiol and androstenedione (pg/ml) by tea intake

 
Soy and tea appear to have independent effects on plasma estrone levels. In our previous study, estrone levels were 15% lower among individuals in the highest quartile of soy protein intake compared with those in the lower quartiles of intake (P = 0.047) when tea intake was not considered in the analysis (5). After adjustment for tea intake and other covariates in this analysis, the effect of soy on estrone levels diminished slightly; estrone levels were 14% lower among individuals in the highest quartile of soy protein intake (27.7 pg/ml) compared with those in the lower quartiles of intake (32.2 pg/ml) (P = 0.08). Soy intake did not have significant effect on estradiol (P = 0.23) or androstenedione levels (P = 0.86) after adjusting for intake of tea and other covariates (data not shown).

Geometric mean hormone levels by tea intake, according to COMT genotype, are presented in Table III. Among women who were homozygous for the COMT H allele and those who were heterozygous for the COMT L allele, plasma estrone levels were 10 and 16% lower, respectively, in regular green tea drinkers compared with non-tea drinkers, whereas the corresponding levels were 20 and 18% higher in regular black tea drinkers (P for tea effect = 0.03). COMT genotype did not have a significant effect on plasma estrone levels (P for COMT effect = 0.69), and did not significantly influence the tea–estrone association (P for interaction effect = 0.93). Similarly, COMT genotype did not significantly influence plasma estradiol or androstenedione levels; and it did not modify the tea–estradiol or tea–androstenedione associations (Table III).


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Table III. Adjusteda geometric mean circulating levels of estrone, estradiol and androstenedione (pg/ml) by tea intake and COMT genotype

 

    Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In this cross-sectional study of postmenopausal Chinese women in Singapore, we found that tea drinking significantly influences plasma estrogen levels and that these levels are influenced differentially by the type of tea used. Additionally, the COMT genotype, a measure of one's ability to eliminate tea polyphenols, did not influence the tea–blood hormone associations. We interpret these two findings to suggest that the differential effects of black and green tea on hormone levels are unlikely to be due to tea polyphenols, but rather due to some other, yet to be identified constituents of tea.

Before discussing our findings, some methodologic limitations of this investigation should be considered. An original intent of this cross-sectional study was to identify dietary and non-dietary determinants of blood estrogen levels in postmenopausal Chinese women (5). When we started this project, we did not know that green tea and black tea would differentially influence blood hormone levels. Thus, by default, our findings in this report fall under the category of ‘hypothesis generation’. In addition to including a larger sample size, future studies may be designed in a way to ensure that the numbers of non-tea drinkers, green tea drinkers only and black tea drinkers only are more balanced.

Despite the modest sample size of this study and the preliminary nature of its observations, the high degree of internal consistency of our findings, coupled with biological plausibility tend to strengthen the study hypothesis, that the type of tea may matter. Compared with non- and irregular tea drinkers in particular, we found reduction in circulating levels of both estrone (–13%) and estradiol (–8%) among weekly/daily green tea drinkers and increase in both estrone (+19%) and estradiol (+10%) levels among weekly/daily black tea drinkers. Both findings are statistically significant (P = 0.02 and P = 0.03, respectively) (Table II, bottom). A similar pattern of differences in androstenedione levels by tea intake was found. It should be noted that we had previously reported no association between tea intake and blood estrogen levels and this was owing to ignoring the type of tea in our analysis (5). The present analysis shows that an association between tea intake and blood hormone levels may be missed if the type of tea and frequency of tea intake are not considered simultaneously. Data in support of modulating effects of tea on plasma hormone levels lend credibility to observational findings of a tea–breast cancer association (2) since there is now compelling evidence that endogenous hormones, especially estrogens, play a critical role in the etiology of breast cancer (13).

The differing effects of green and black tea on circulating estrogen levels have corroborative support from human and non-human studies. In a study of premenopausal women in Japan, Nagata et al. (6) reported a significant inverse association between green tea intake and follicular phase blood estradiol levels (black tea intake was very low in this Japanese population). In rodent studies, green tea extract and epigallocatechin gallate (EGCG) were associated with inhibitory effects on aromatase activity (14,15) such that aromatase activity was inhibited by 56% when mice were dosed with 12.5 mg/kg of EGCG (14). This level of EGCG intake is achievable in humans as one cup (240 ml) of green tea contains up to 200 mg of EGCG (16). Since levels of EGCG are substantially higher in green tea than in black tea (17), it is plausible that the lower estrogen levels associated with green intake tea is explained partly by the inhibitory effects of EGCG on aromatase activity and hence the synthesis of estrogen. However, black tea also contains EGCG and other tea catechins, though in lower levels and thus it is not obvious why estrogen levels are not lower in regular black tea drinkers compared with non-regular tea drinkers. In fact, black tea appeared to have deleterious effects on circulating hormone levels in a cross-sectional study of >500 Dutch women, who presumably consumed only black tea (18). In that study, serum prolactin levels increased significantly with increasing levels of black tea intake (18). Although blood estrogen levels were not measured in this study, breast cancer risk was found to increase significantly with increasing prolactin levels in the Nurses Health Study (19).

Motivated by our previous finding that the inverse association between tea and breast cancer risk is found mainly among women who were heterozygous for the COMT L allele (i.e. those less efficient in eliminating tea polyphenols) (4), we investigated the tea–plasma hormone associations by COMT genotype. Contrary to our findings in relation to breast cancer risk (4), the COMT genotype did not significantly influence the tea–hormone associations in this analysis. Specifically, plasma estrone, estradiol and androstenedione levels were consistently lower among green tea drinkers while they were consistently higher among black tea drinkers irrespective of COMT genotype (Table III). We believe that our recent finding of an upregulatory effect of black tea and a downregulatory effect of green tea on circulating estrogen levels provides a cogent explanation for the paradoxical findings of our first two papers on tea (2,4). These results suggest that tea polyphenols are not the constituents, in black tea and green tea, responsible for the hormonal effects of tea that we and others (6,14,15,18) have identified in human and rodent studies. The differential effects on breast cancer protection between green tea versus black tea, despite comparable levels of antioxidative tea polyphenols between the two types of tea (20), may lie in the possibility that they possess opposing effects on sex-steroid hormones. Green tea may have strong beneficial effects on the breast through both its antioxidant properties and its downregulatory effects on estrogens. In contrast, while black tea possesses antioxidant effects, it nonetheless exhibits no downregulatory (or may be upregulatory) effects on blood estrogen levels. These latter opposing effects of black tea, if confirmed, may help to explain the overall weaker effect of black tea on breast cancer risk.

The sample size of this cross-sectional study is modest and thus we view these results as preliminary and requiring confirmation in larger studies. Further investigations of possible hormonal effects of green tea and black tea should provide a better understanding of the role of these teas in the etiology of breast cancer and will complement epidemiologic investigations on the relationship between tea intake and breast cancer risk.


    Acknowledgments
 
We thank Ms Siew-Hong Low of the National University of Singapore for supervising the field work of the Singapore Chinese Health Study. The Singapore Chinese Health Study has been supported by grants R01 CA55069, R35 CA53890 and R01 CA80205 from the National Cancer Institute, Bethesda, Maryland. A.H.W. is supported, in part, by the California Breast Cancer Research Program (9PB-0089) and the Susan G.Komen Breast Cancer Foundation (POP0201896).


    References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received October 4, 2004; revised November 15, 2004; accepted January 11, 2005.





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