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Urinary estrogen metabolites in women at high risk for breast cancer. Im A, Vogel VG, Ahrendt G, Lloyd S, Ragin C, Garte S, Taioli E. Magee/UPCI Breast Cancer Prevention Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. Carcinogenesis. 2009 Sep;30(9):1532-5. OBJECTIVE: This study explored whether average urinary estrogen metabolites in breast cancer high-risk women can be used to identify a subgroup of women at particularly high risk to develop breast cancer, to which prevention strategies should be addressed. METHODS: The population consisted of 77 high-risk women, 30 breast cancer patients and 41 controls. All subjects answered a standardized questionnaire; height and weight and spot urine samples were also obtained. Urine hydroxyestrogen metabolites were measured in triplicate by enzyme immunoassay, and the estrogen metabolite ratios for each individual were calculated. RESULTS: The 2:16 OHE ratio (2-hydroxyestrone/16-alpha-hydroxyestrone) in women at high risk for breast cancer was similar to that observed in the breast cancer group (1.76 +/- 2.33 versus 1.29 +/- 0.80) and lower than in controls (2.47 +/- 1.14; P = 0.00). At the multivariate linear regression model, the 2:16 OHE ratio was significantly associated with diagnosis (P = 0.000 for both the high risk and breast cancer group versus the controls) and body mass index (P = 0.005), but not with age (P = 0.604), or smoking history (P = 0.478). CONCLUSIONS: This study suggests that lower urinary 2:16 OHE ratios are predictors of breast cancer risk. Profiling estrogen metabolites may identify women who are more probably to develop breast cancer within a population of women with known risk factors and may help to further elucidate the clinical relevance of urinary 2:16 OHE ratios as clinical markers and prognostic indicators in this population. PMID: 19502596 [PubMed - indexed for MEDLINE] Urinary estrogen metabolites and prostate cancer: a case-control study and meta-analysis. Barba M, Yang L, Schünemann HJ, Sperati F, Grioni S, Stranges S, Westerlind KC, Blandino G, Gallucci M, Lauria R, Malorni L, Muti P. Department of Epidemiology, National Cancer Institute Regina Elena, Rome, Italy. J Exp Clin Cancer Res. 2009 Oct 8;28:135. OBJECTIVE: To investigate prostate cancer (Pca) risk in relation to estrogen metabolism, expressed as urinary 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestrone (16alpha-OHE1) and 2-OHE1 to 16alpha-OHE1 ratio. METHODS: We conducted a case-control study within the Western New York Health Cohort Study (WNYHCS) from 1996 to 2001. From January 2003 through September 2004, we completed the re-call and follow-up of 1092 cohort participants. Cases (n = 26) and controls (n = 110) were matched on age, race and recruitment period according to a 1:4 ratio. We used the unconditional logistic regression to compute crude and adjusted odds ratios (OR) and 95% confident interval (CI) of Pca in relation to 2-OHE1, 16alphaOHE1 and 2-OHE1 to 16alpha-OHE1 by tertiles of urine concentrations (stored in a biorepository for an average of 4 years). We identified age, race, education and body mass index as covariates. We also conducted a systematic review of the literature which revealed no additional studies, but we pooled the results from this study with those from a previously conducted case-control study using the DerSimonian-Laird random effects method. RESULTS: We observed a non-significant risk reduction in the highest tertile of 2-OHE1 (OR 0.72, 95% CI 0.25-2.10). Conversely, the odds in the highest tertile of 16alpha-OHE1 showed a non-significant risk increase (OR 1.76 95% CI 0.62-4.98). There was a suggestion of reduced Pca risk for men in the highest tertile of 2-OHE1 to 16alpha-OHE1 ratio (OR 0.56, 95% CI 0.19-1.68). The pooled estimates confirmed the association between an increased Pca risk and higher urinary levels of 16alpha-OHE1 (third vs. first tertile: OR 1.82, 95% CI 1.09-3.05) and the protective effect of a higher 2-OHE 1 to 16alpha-OHE1 ratio (third vs. first tertile: OR 0.53, 95% CI 0.31-0.90). CONCLUSION: Our study and the pooled results provide evidence for a differential role of the estrogen hydroxylation pathway in Pca development and encourage further study. PMID: 19814782 [PubMed - indexed for MEDLINE] Click for FREE full text article Ethnicity, body size, and estrogen levels in postmenopausal Hispanic and non-Hispanic white women. Wacker M, Risendal B, Westerlind K, Lezotte D, Byers T. University of Colorado Denver, Aurora, Colorado 80045, USA. J Womens Health (Larchmt). 2009 Apr;18(4):487-91. BACKGROUND: Hispanic women are at lower risk for incident breast cancer, but the reasons for this lower risk are unknown. Among postmenopausal women, breast cancer risk is inversely associated with circulating levels of 2-hydroxyestrone but directly associated with levels of 16alpha-hydroxyestrone, according to most studies. Likewise, according to most research, the ratio of 2-hydroxyestrone/16alpha-hydroxyestrone is, therefore, inversely associated with breast cancer risk. METHODS: We measured levels of these two circulating estrones as well as estradiol in 40 Hispanic women and 40 non-Hispanic white women who were all postmenopausal and not taking hormones. RESULTS: Compared with non-Hispanic white women, Hispanic women had 69% higher circulating levels of 2-hydroxyestrone (p = 0.04), and 10% lower levels of 16alpha-hydroxyestrone (p = 0.09). Consequentially, Hispanic women had more favorable estrogen profiles than non-Hispanic white women, with an 89% higher 2:16 ratio (p = 0.01). This finding was not substantially affected by adjustment for other breast cancer risk factors, including matching on body mass index (BMI). CONCLUSIONS: This ethnic difference in estrogen profile requires further research to establish whether there is a causal relationship to breast cancer risk that may, at least partially, explain why postmenopausal Hispanic women have a lower incidence of breast cancer. PMID: 19361315 [PubMed - indexed for MEDLINE] A hormonal association between estrogen metabolism and proliferative thyroid disease. Chan EK, Sepkovic DW, Yoo Bowne HJ, Yu GP, Schantz SP. Department of Otolaryngology-Head and Neck Surgery, New York Medical College, New York, New York 10003, USA. echan@nyee.edu Otolaryngol Head Neck Surg. 2006 Jun;134(6):893-900 OBJECTIVE: To illustrate a relationship between proliferative thyroid disease and estrogen metabolism through the analysis of urinary estrogen metabolites. STUDY DESIGN AND SETTING: Case-control study of 49 subjects with proliferative thyroid disorders and matching them to 49 controls. Urinary estrogen metabolite ratios were obtained, measuring 2-hydroxyestrone, an anti-proliferative metabolite, to 16alpha-hydroxyestrone, a proliferative metabolite. The patients were stratified into low (0 to 1.00), medium (1.01 to 2.00), or high (>2.00) groups according to their estrogen metabolite ratio. RESULTS: Fifty-one percent (25 of 49) of the cases had a low 2/16 ratio compared to 31% (15 of 49) in the control group while 20% (10 of 49) of the control group had a high 2/16 ratio as compared to 8% (4 of 49) in the case group (P value < 0.05). CONCLUSIONS: Increased 16alpha-hydroxyestrone activity compared to 2-hydroxyestrone activity appears to be associated with proliferative thyroid disease. SIGNIFICANCE: Further study of estrogen metabolites in relation to proliferative thyroid disease is warranted and may lead to implications for new treatment modalities for proliferative thyroid disease. EBM RATING: B-3b. PMID: 16730526 [PubMed - indexed for MEDLINE]
Estrogen metabolites and systolic blood pressure in a population-based sample of postmenopausal women. Masi CM, Hawkley LC, Berry JD, Cacioppo JT. Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. cmasi@medicine.bsd.uchicago.edu J Clin Endocrinol Metab. 2006 Mar;91(3):1015-20. Epub 2005. CONTEXT: Lower systolic blood pressure (SBP) and lower rates of coronary heart disease among premenopausal women compared with similarly aged men and postmenopausal women suggest that female sex hormones may confer cardiovascular protection. 2-Hydroxyestradiol, a product of 17beta-estradiol oxidative metabolism, inhibits the proliferation of vascular smooth muscle cells in vitro. The other major product of 17beta-estradiol oxidative metabolism, 16alpha-hydroxyestradiol, does not demonstrate similar inhibitory effects. Concentrations of 2-hydroxyestrone (2-OHE) and 16alpha-hydroxyestrone (16-OHE) in urine reflect the relative activity of the 2- and 16alpha-hydroxylation pathways of 17beta-estradiol. OBJECTIVE: The objective of this study was to determine the relationship between SBP and the ratio of 2-OHE to 16-OHE in urine. DESIGN AND PARTICIPANTS: This was a cross-sectional study of 80 postmenopausal women living in Cook County, Illinois. SETTING: This study was performed in an academic clinical laboratory. MAIN OUTCOME MEASURE: The main outcome measure was SBP. RESULTS: Women taking hormone replacement therapy had higher levels of urinary 2-OHE and 16-OHE, but their mean 2:16-OHE ratio and SBP did not differ from that of women not taking hormone replacement therapy. In a multivariate regression model that controlled for age, body mass index, race/ethnicity, and antihypertensive medication use, a sd increase in the 2:16-OHE ratio was associated with a 6.7-mm Hg decrease (P < 0.05) in SBP. CONCLUSIONS: The ratio of urinary 2-OHE to 16-OHE is a significant predictor of SBP among postmenopausal women and may reflect the effects of 2-hydroxyestradiol, a potent inhibitor of vascular smooth muscle cell proliferation. PMID: 16384842 [PubMed - indexed for MEDLINE]
Estrogen metabolism and breast cancer. Kabat GC, O'Leary ES, Gammon MD, Sepkovic DW, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Bradlow HL. Department of Preventive Medicine, School of Medicine, Stony Brook University, New York, USA. gck1@optonline.net Epidemiology.2006 Jan;17(1):80-8. BACKGROUND: Specific pathways involved in estrogen metabolism may play a role in the etiology of breast cancer. We used data from a large population-based case-control study to assess the association of the urinary estrogen metabolites 2-hydroxyestrone (2-OHE1), 16alpha-hydroxyestrone (16-OHE1), and their ratio (2/16) with both invasive and in situ breast cancer. METHODS: Study participants from the Long Island Breast Cancer Study Project provided a spot urine specimen and completed a comprehensive interviewer-administered questionnaire. Women who used exogenous hormones or who took tamoxifen in the 6 months before urine collection were excluded from the analysis, leaving 269 invasive cases, 158 in situ cases, and 326 controls. Unconditional logistic regression was used to obtain adjusted odds ratios (ORs) for invasive and in situ breast cancer, separately, in relation to tertiles of the individual metabolites (standardized for creatinine) and the 2/16 ratio, stratified by menopausal status. RESULTS: The OR for invasive breast cancer was inversely associated with the 2/16 ratio among premenopausal women (OR = 0.50 for extreme tertiles; 95% confidence interval = 0.25-1.01). ORs ranged from 0.32 to 0.60 when women were stratified by whether cases had received chemotherapy within 6 months before urine collection and by estrogen receptor status. In postmenopausal women, there was a slight reduction in the odds ratio for invasive cancer with high levels of the 2/16 ratio (OR = 0.78; 95% confidence interval = 0.46-1.33). Neither the individual metabolites nor the ratio were associated with in situ breast cancer. CONCLUSION: These data provide support for the hypothesis that the 2/16 ratio is associated with reduced breast cancer risk. The most consistent associations were observed with invasive cancer in premenopausal women. PMID: 16357599 [PubMed - indexed for MEDLINE]
Teas J, Cunningham JE, Fowke JH, Nitcheva D, Kanwat CP, Boulware RJ, Sepkovic DW, Hurley TG, Hebert JR. Arnold School of Public Health, University of South Carolina, 2221 Devine Street Room 230, Columbia, SC 29208, USA. jane.teas@sc.edu Cancer Detect Prev. 2005;29(6):494-500. Epub 2005 Nov 10. INTRODUCTION: Estrogen metabolites have been linked to risk of breast cancer, and we were interested in whether they are associated with prostate specific antigen (PSA) and other factors associated with prostate cancer. African-American (AA) men in South Carolina have among the highest prostate cancer rates in the world, and thus provide an ideal population in which to investigate this hypothesis. METHODS: We recruited AA men attending prostate cancer screenings in and around Columbia, South Carolina. Because very few men had elevated PSAs, we restricted our study to the 77 men whose PSA was below the cutpoint used by the screening program to indicate need for diagnostic workup. These men provided spot urine samples and answered demographic and lifestyle questions including self-reported body weight, height, exercise, tobacco use, medications, cancer history and age. Levels of urinary 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio (2/16) and blood PSA levels were determined. RESULTS: After adjusting for a statistically significant interaction between age and BMI, we found a reduction of 14.2% in 2-OHE1 for each 1.0 ng/ml increase in PSA (p=0.05). For obese AA men only (BMI> or =30 kg/m2), 2-OHE1 increased by 36% for each decade of age (p=0.009). CONCLUSIONS: Estrogen metabolites may be related to PSA level in AA men. Older men with BMIs greater than 30 kg/m2 had an unexpected increase in 2-OHE1, suggesting a dysregulation of this estrogen metabolism pathway. Further studies of estrogen metabolites may provide insights into prostate cancer risk factors. PMID: 16289388 [PubMed - indexed for MEDLINE]
The relationship between physical activity and 2-hydroxyestrone, 16alpha-hydroxyestrone, and the 2/16 ratio in premenopausal women (United States). Bentz AT, Schneider CM, Westerlind KC. Sport and Exercise Science, BNCC Campus Box 6, University of Northern Colorado, Greeley, CO 80639, USA. ann.bentz@unco.edu Cancer Causes Control. 2005 May;16(4):455-61. OBJECTIVES: Estrogen is metabolized in the body through two mutually exclusive pathways yielding metabolites with different biological activities: the low estrogenic 2-hydroxyestrone (2-OHE1) and the highly estrogenic 16alpha-hydroxyestrone (16alpha-OHE1). The ratio of these metabolites (2/16) may be predictive of risk for developing breast cancer. Early evidence has demonstrated that exercise may alter estrogen metabolism to favor the weak estrogen, 2-OHE1. METHODS: Seventy-seven eumenorrheic females completed physical activity logs for two weeks prior to providing a luteal phase urine sample. Concentrations of 2-OHE1 and 16alpha-OHE1 were measured and the 2/16 ratio computed. Hierarchical regression, controlling for age and body mass index (BMI), was used to determine relationships between estrogen metabolites and daily physical activity. RESULTS: Regression analyses indicated significant positive relationships between physical activity and 2-OHE1 and the 2/16 ratio (p < 0.05) that appears to be independent of BMI. 16alpha-OHE1 was not significantly related to physical activity. CONCLUSION: These results indicate that physical activity may modulate estrogen metabolism to favor the weak estrogen, 2-OHE1, thus producing a higher 2/16 ratio. This alteration in estrogen metabolism may represent one of the mechanisms by which increased physical activity reduces breast cancer risk. PMID: 15953988 [PubMed - indexed for MEDLINE]
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