Urinary 2-Hydroxyestrone/16 -Hydroxyestrone Ratio and Risk of Breast Cancer in Postmenopausal Women

Ursin, Giske; London, Stephanie J.; Stanczyk, Frank Z.; Gentzschein, Elisabet; Paganini‐Hill, Annlia; Ross, Ronald K.; Pike, Malcolm C.

doi:10.1093/jnci/91.12.1067

Cited by 113 publications

(57 citation statements)

References 48 publications

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“…Most but not all case-control studies investigating the role of estrogen metabolism in postmenopausal breast cancer risk support the hypothesis that greater 2-OHE1 levels protect against breast cancer while greater 16a-OHE1 may increase risk. [26][27][28][29][30][31] Differences in these findings may be an artifact of study design, including small sample sizes (usually less than 50 cases), noncomparable controls and the use of spot urine samples to measure metabolite levels, which may be sensitive to changes in excretory patterns and function. Moreover, the presence of the tumor or an endocrine response to treatment, both of which may be present in women recruited after diagnosis, may alter metabolite levels.…”

Section: Discussionmentioning

confidence: 99%

“…16a-OHE1 retains potent hormonal activities by binding strongly to the estrogen receptor. 22 Laboratory data [23][24][25] and some but not all epidemiologic studies [26][27][28][29][30][31][32][33][34] suggest a positive association between 16a-OHE1 levels and breast cancer risk. In contrast, 2-OHE1 binds to the estrogen receptor with reduced affinity 35 and because of O-methylation is cleared rapidly from circulation.…”

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confidence: 99%

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Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer

Modugno

Kip

Cochrane

et al. 2005

Intl Journal of Cancer

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Hormone therapy (HT) and body mass index (BMI) have been associated with postmenopausal breast cancer. Because estrogen metabolism may affect breast cancer risk and can be altered by weight and HT, it might play a role in the HT-BMI-breast cancer associations. We undertook a nested case-control study within the Observational Study of the Women's Health Initiative. Baseline levels of 2-and 16a-hydroxy estrone (2-OHE1 and 16a-OHE1) were measured in 200 women who developed breast cancer during follow-up and 200 healthy controls matched to cases by ethnicity, enrollment date, clinic site, type of HT and years since menopause. Wilcoxon nonparametric tests were used to compare estrogen metabolite levels between cases and controls. Conditional logistic regression was used to assess the relationship between BMI, estrogen metabolites and breast cancer risk. 16a-OHE1 levels were modestly but significantly higher in HT users among cases (median 356 pg/ml vs. 315 pg/ml) and controls (354 pg/ml vs. 298 pg/ml). 2-OHE1 levels were substantially and significantly higher in HT users among cases (369 pg/ml vs. 125 pg/ml) and controls (347 pg/ml vs. 134 pg/ml). For non-HT users only, greater BMI and higher 16a-OHE1 levels were individually and jointly associated with increased breast cancer risk (OR for women with high BMI and high 16a-OHE1 compared to those with low BMI and low 16a-OHE1 5 3.51, 95% CI 5 1.34-9.16). No associations between BMI, estrogen metabolism and breast cancer risk were found for HT users. Estrogen metabolism differs according to both BMI and HT use, potentially explaining the interaction between BMI and HT in relation to breast cancer risk. ' 2005 Wiley-Liss, Inc.Key words: breast neoplasms; hormone therapy; estrogen metabolism; body mass index; obesity The Women's Health Initiative (WHI) clinical trial recently confirmed observational study findings 1,2 that progestin-containing hormone therapy (HT) formulations are associated with an increased risk of postmenopausal breast cancer.3 Elevated circulating estrogen levels may underlie this association, as substantial data, including markers of long-term estrogen exposure, 4 implicate estrogen in the etiology of postmenopausal breast cancer. However, for a given dose of estrogen, estrogen-only HT formulations appear to impart less risk than combined estrogen and progestin therapies. 1,3,[5][6][7][8] In particular, the WHI clinical trial reported no increase in risk associated with an estrogen-only formulation, 8 but a 24% increase in risk among women assigned to a combination estrogen-progestin formulation compared to placebo.3 Interestingly, this increase is less than expected, given the magnitude of the increase in circulating estrogens resulting from oral estrogen preparations 9,10 and among studies that associate higher blood levels of estrogen with increased breast cancer risk. 11,12Body size has also been implicated in postmenopausal breast cancer.13,14 For example, risk increases by 3% for each kilogram per meter square increase in body mass index (BMI)...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer

Modugno

Kip

Cochrane

et al. 2005

Intl Journal of Cancer

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“…However, the relationship between urinary 2OHE 1 :16OHE 1 ratios and breast cancer risk is not clear. Although women with breast cancer had lower urinary ratios of 2OHE 1 :16αOHE 1 in several small case-control studies [35][36][37], larger case-control and prospective cohort studies have not found significant associations between urinary 2OHE 1 :16αOHE 1 ratios and breast cancer risk [38][39][40].…”

Section: Effects Of Indole-3-carbinol On Estrogen Metabolismmentioning

confidence: 99%

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Higdon

Delage

Williams

et al. 2007

Pharmacological Research

916

697

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Cruciferous vegetables are a rich source of glucosinolates and their hydrolysis products, including indoles and isothiocyanates, and high intake of cruciferous vegetables has been associated with lower risk of lung and colorectal cancer in some epidemiological studies. Glucosinolate hydrolysis products alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers, but evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent. Organizations such as the National Cancer Institute recommend the consumption of 5-9 servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Isothiocyanates and indoles derived from the hydrolysis of glucosinolates, such as sulforaphane and indole-3-carbinol (I3C), have been implicated in a variety of anticarcinogenic mechanisms, but deleterious effects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure. Epidemiological studies indicate that human exposure to isothiocyanates and indoles through cruciferous vegetable consumption may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body. Cooking procedures also affect the bioavailability and intake of glucosinolates and their derivatives. Supplementation with I3C or the related dimer 3,3′-diindolylmethane (DIM) alters urinary estrogen metabolite profiles in women, but the effects of I3C and DIM on breast cancer risk are not known. Small preliminary trials in humans suggest that I3C supplementation may be beneficial in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis, but larger randomized controlled trials are needed.

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“…Our study also showed that 2(OH)-E and 16a(OH)-E 1 were stable enough to be measured in urine samples stored at )20°C for more 25 years without any added preserving agents. Absolute values in the frozen samples were not different from those in fresh urine samples from post-menopausal women (average data within ''normal'' post-menopausal range on fresh urine samples were provided by the kit manufacturer), or in urine samples that were stored for much shorter periods of time, measured with the same method [8,[24][25][26]. The apparent stability of hormones during storage time, even at a temperature of )20°C, may be an important issue for prospective epidemiological studies in which biological samples are stored frozen over many years.…”

Section: Discussionmentioning

confidence: 99%

Reproducibility over time of measurements of androgens, estrogens and hydroxy estrogens in urine samples from post-menopausal women

et al. 2002

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Abstract. Sex steroid concentrations in urine samples from post-menopausal women have been associated with risk of various chronic diseases. The basic requirement for the assessment of risk in such largescale epidemiological studies is that subjects be ranked accurately by their average, long-term hormone levels. We examined the reproducibility over time of measurements of urinary testosterone (T), 5a-androstane-3a, 17b-diol (ADIOL), estrone (E 1 ), estradiol (E 2 ), 2-hydroxy estrone and 2-hydroxy estradiol, (2(OH)-E), 16a-hydroxyestrone (16a(OH)-E 1 ) and the ratio of 2(OH)-E and 16a(OH)-E 1 , in a representative sub-sample of post-menopausal women (n ¼ 43) participating in an ongoing prospective cohort study. Women collected three first morning urine voids on different occasions, with average time difference between the first and the third urine sample of 5.1 years. T, ADIOL, E 1 and E 2 were measured by radio immunoassay after enzymatic hydrolysis, solidphase extraction and HPLC purification of the samples, while 2(OH)-E and 16a(OH)-E 1 were assayed by solid-phase enzyme immunoassay after enzymatic hydrolysis. Intra-class correlation co-efficients (ICCs) over time were very good for T (r ¼ 0.85), acceptable for E 2 , E 1 and ADIOL (r > 0.55), but low for 2(OH)-E, 16a(OH)-E 1 and their ratio (r < 0.46). The adjustment for creatinine concentrations did not increase these correlations.Key words: Androgens, Estrogens, Hydroxy estrogens, Post-menopausal women, Reproducibility, Urine Abbreviations: ADIOL = 5a-androstane-3a, 17b-diol; E 2 = estradiol; E 1 = estrone; 2(OH)-E = 2-hydroxy estrone and 2-hydroxy estradiol; 16a(OH)-E 1 = 16a-hydroxyestrone; T = testosterone

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Urinary 2-Hydroxyestrone/16 -Hydroxyestrone Ratio and Risk of Breast Cancer in Postmenopausal Women

Abstract: This study does not support the hypothesis that the ratio of the two hydroxylated metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer.

Cited by 113 publications

References 48 publications

Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer

Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Reproducibility over time of measurements of androgens, estrogens and hydroxy estrogens in urine samples from post-menopausal women

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