Dr. Ron’s Research Review – April 25, 2012

This week’s research review focuses on coffee and hormones.

Polyphenolic components in coffee inhibit human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens. (Zhu, Wang et al. 2009)

Coffee intake was significantly associated with lower luteal total and free estradiol levels, but not luteal progesterone levels. Among the postmenopausal women, there was a positive association between caffeine and coffee intake and SHBG levels. (Kotsopoulos, Eliassen et al. 2009)

The Rancho Bernardo study found a positive association of caffeine with estrone and its inverse association with bioavailable testosterone in postmenopausal women. (Ferrini and Barrett-Connor 1996)

A recent meta-analysis found that coffee consumption may reduce the total cancer incidence and it also has an inverse association with some type of cancers. (Yu, Bao et al. 2011)

A recent study found that high daily intake of coffee was associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women. (Li, Seibold et al. 2011)

Trigonelline, a niacin-related compound found in coffee, however, stimulated MCF-7 cell proliferation. (Allred, Yackley et al. 2009)

A prospective analysis of 47,911 men in the Health Professionals Follow-up observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee. (Wilson, Kasperzyk et al. 2011)

In a case-controlled human study, those who drank the most coffee cut their risks of diabetes by 67% when compared to those that did not drink coffee. (Zhang, Lee et al. 2011)

Dr. Ron


Abstracts

Trigonelline is a novel phytoestrogen in coffee beans

            (Allred, Yackley et al. 2009) Download

Drinking coffee has been associated with the development of several endocrine-related cancers. The interpretation of these data has often been limited to the role that caffeine plays. Trigonelline (Trig), a niacin-related compound, is a natural constituent of coffee accounting for approximately 1% dry matter in roasted beans. Studies exploring the effects of this bioactive compound on mammalian cells are limited. The initial purpose of our studies was to determine whether Trig alters the actions of estradiol (E(2)), using proliferation of estrogen-dependent human breast cancer (MCF-7) cells as a model system. When cells were cotreated with suboptimal doses of E(2) (10 pmol/L) and Trig (100 pmol/L), an additive enhancement of MCF-7 growth was observed. In the absence of E(2), Trig stimulated MCF-7 cell proliferation in a dose-responsive manner and significantly enhanced cell growth at concentrations as low as 100 pmol/L. Cotreatment of MCF-7 cells with Trig and ICI 182,780, an estrogen receptor (ER) antagonist, inhibited Trig-induced cell proliferation. Trig treatment also induced activation of estrogen response element reporter assays in MCF-7 cells and increased expression of ER target genes (pS2, progesterone receptor, and cyclin D1) similar to E(2). While our data demonstrate that Trig activates the ER, competitive binding assays showed that Trig does not compete E(2) off of the ER at any concentration. This suggests that Trig is activating the ER through a separate mechanism. Collectively, these data demonstrate that Trig even at low concentrations stimulates MCF-7 cell growth and that this effect is mediated through ER, clearly identifying Trig as a novel phytoestrogen.

Caffeine intake and endogenous sex steroid levels in postmenopausal women. The Rancho Bernardo Study

            (Ferrini and Barrett-Connor 1996) Download

Caffeine intake has been associated with risk of osteoporosis, breast cancer, endometriosis, and fibrocystic breast disease and has been hypothesized to exert its effects through alteration of endogenous hormone levels. This study examined the cross-sectional association of caffeine intake with endogenous androgens, estrogens, and sex hormone-binding globulin in 728 white postmenopausal women aged 42-90 years in the Rancho Bernardo community-based study in 1984-1987. Caffeine intake was inversely associated with age and waist/hip ratio and positively associated with alcohol consumption. Significant inverse associations were noted between caffeine intake and bioavailable testosterone, which persisted after adjustment for age, waist/hip ratio, body mass index, alcohol intake, cigarette smoking, and physical activity (r = -0.10, p = 0.02). At high doses (equivalent to more than 2 cups of coffee or four cans of caffeinated soda daily), caffeine intake was positively associated with plasma estrone before and after adjustment for confounders (r = 0.26, p = 0.05). Sex hormone-binding globulin levels were positively associated with increasing caffeine intake (adjusted r = 0.09, p = 0.03). The positive association of caffeine with estrone and its inverse association with bioavailable testosterone suggest that caffeine's reported association with several chronic conditions may be mediated by an effect on endogenous sex steroids.

Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women

            (Kotsopoulos, Eliassen et al. 2009) Download

BACKGROUND: Circulating estrogens and androgens are important factors in the development of various female cancers. Caffeine intake may decrease risk of breast and ovarian cancer, although the data are not entirely consistent. Whether or not caffeine affects cancer risk by altering sex hormone levels is currently unknown. METHODS: We examined the relationship of caffeine, coffee, decaffeinated coffee, and tea with plasma concentrations of estrogens, androgens, progesterone, prolactin, and sex hormone-binding globulin (SHBG) in 524 premenopausal and 713 postmenopausal women from the Nurses' Health Study (NHS) and NHSII. RESULTS: In premenopausal women, caffeine intake was inversely associated with luteal total and free estradiol, and positively associated with luteal progesterone levels (P-trend = .02, .01, .03, respectively). Coffee intake was significantly associated with lower luteal total and free estradiol levels, but not luteal progesterone levels (P-trend = .007, .004, .20, respectively). Among the postmenopausal women, there was a positive association between caffeine and coffee intake and SHBG levels (P-trend = .03 and .06, respectively). No significant associations were detected with the other hormones. CONCLUSIONS: Data from this cross-sectional study suggest that caffeine may alter circulating levels of luteal estrogens and SHBG, representing possible mechanisms by which coffee or caffeine may be associated with pre- and postmenopausal malignancies, respectively. Future studies evaluating how caffeine-mediated alterations in sex hormones and binding protein levels affect the risk of female cancers are warranted.


Coffee consumption modifies risk of estrogen-receptor negative breast cancer

            (Li, Seibold et al. 2011) Download

INTRODUCTION: Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes. METHODS: Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate. RESULTS: In the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR</= 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR</= 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004). CONCLUSIONS: A high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women.

Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study

            (Wilson, Kasperzyk et al. 2011) Download

Background Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer. Methods We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests. Results The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, P(trend) = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, P(trend) = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (>/=6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years. Conclusions We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.

Coffee consumption and risk of cancers: a meta-analysis of cohort studies

            (Yu, Bao et al. 2011) Download

BACKGROUND: Coffee consumption has been shown to be associated with cancer of various sites in epidemiological studies. However, there is no comprehensive overview of the substantial body of epidemiologic evidence. METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded and bibliographies of retrieved articles. Prospective cohort studies were included if they reported relative risks (RRs) and corresponding 95% confidence intervals (CIs) of various cancers with respect to frequency of coffee intake. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with 1 cup/day increment of coffee consumption. RESULTS: 59 studies, consisting of 40 independent cohorts, met the inclusion criteria. Compared with individuals who did not or seldom drink coffee per day, the pooled RR of cancer was 0.87 (95% CI, 0.82-0.92) for regular coffee drinkers, 0.89 (0.84-0.93) for low to moderate coffee drinkers, and 0.82 (0.74-0.89) for high drinkers. Overall, an increase in consumption of 1 cup of coffee per day was associated with a 3% reduced risk of cancers (RR, 0.97; 95% CI, 0.96-0.98). In subgroup analyses, we noted that, coffee drinking was associated with a reduced risk of bladder, breast, buccal and pharyngeal, colorectal, endometrial, esophageal, hepatocellular, leukemic, pancreatic, and prostate cancers. CONCLUSIONS: Findings from this meta-analysis suggest that coffee consumption may reduce the total cancer incidence and it also has an inverse association with some type of cancers.

Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study

            (Zhang, Lee et al. 2011) Download

BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation.

Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee

            (Zhu, Wang et al. 2009) Download

In the present study, we investigated the inhibitory effect of three catechol-containing coffee polyphenols, chlorogenic acid, caffeic acid and caffeic acid phenethyl ester (CAPE), on the O-methylation of 2- and 4-hydroxyestradiol (2-OH-E(2) and 4-OH-E(2), respectively) catalyzed by the cytosolic catechol-O-methyltransferase (COMT) isolated from human liver and placenta. When human liver COMT was used as the enzyme, chlorogenic acid and caffeic acid each inhibited the O-methylation of 2-OH-E(2) in a concentration-dependent manner, with IC(50) values of 1.3-1.4 and 6.3-12.5 microM, respectively, and they also inhibited the O-methylation of 4-OH-E(2), with IC(50) values of 0.7-0.8 and 1.3-3.1 microM, respectively. Similar inhibition pattern was seen with human placental COMT preparation. CAPE had a comparable effect as caffeic acid for inhibiting the O-methylation of 2-OH-E(2), but it exerted a weaker inhibition of the O-methylation of 4-OH-E(2). Enzyme kinetic analyses showed that chlorogenic acid and caffeic acid inhibited the human liver and placental COMT-mediated O-methylation of catechol estrogens with a mixed mechanism of inhibition (competitive plus noncompetitive). Computational molecular modeling analysis showed that chlorogenic acid and caffeic acid can bind to human soluble COMT at the active site in a similar manner as the catechol estrogen substrates. Moreover, the binding energy values of these two coffee polyphenols are lower than that of catechol estrogens, which means that coffee polyphenols have higher binding affinity for the enzyme than the natural substrates. This computational finding agreed perfectly with our biochemical data.


References

Allred, K. F., K. M. Yackley, et al. (2009). "Trigonelline is a novel phytoestrogen in coffee beans." J Nutr 139(10): 1833-8.

Ferrini, R. L. and E. Barrett-Connor (1996). "Caffeine intake and endogenous sex steroid levels in postmenopausal women. The Rancho Bernardo Study." Am J Epidemiol 144(7): 642-4.

Kotsopoulos, J., A. H. Eliassen, et al. (2009). "Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women." Cancer 115(12): 2765-74.

Li, J., P. Seibold, et al. (2011). "Coffee consumption modifies risk of estrogen-receptor negative breast cancer." Breast Cancer Res 13(3): R49.

Wilson, K. M., J. L. Kasperzyk, et al. (2011). "Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study." J Natl Cancer Inst.

Yu, X., Z. Bao, et al. (2011). "Coffee consumption and risk of cancers: a meta-analysis of cohort studies." BMC Cancer 11: 96.

Zhang, Y., E. T. Lee, et al. (2011). "Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study." Nutr Metab Cardiovasc Dis 21(6): 418-23.

Zhu, B. T., P. Wang, et al. (2009). "Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee." J Steroid Biochem Mol Biol 113(1-2): 65-74.