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Estrogen Metabolism, Breast Density, and Breast Cancer

Simpson, Jennifer K. (2006) Estrogen Metabolism, Breast Density, and Breast Cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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BACKGROUND: Estrogen metabolites, sex-steroid hormones, and breast density are associated with breast carcinogenesis. OBJECTIVE: Complete a systematic study of the contribution of two biological measures (breast density and hormone metabolism) to an endocrine-based model of breast cancer risk.METHODS: The study groups included breast cancer-free participants (N=282) in the Study of Osteoporotic Fractures (SOF), and participants in the Mammogram and Masses Study (MAMS), inclusive of 176 cases (55 pre-menopausal, 121 post-menopausal) and 380 controls (124 pre-menopausal, 256 postmenopausal). Sex-steroid hormones, percent breast density, serum concentrations of 2-hydroxyestrone (2-OH) and 16 alpha-hydroxyestrone (16alfa-OH), and breast cancer risk factors were evaluated to determine associations.RESULTS: In SOF,16alfa-OH was positively associated with body mass index (BMI) (r=0.162); however, this association was not significant in multivariate analyses that controlled for the serum sex-steroid hormone concentrations (total estradiol, total testosterone, SHBG). Women who reported a surgical menopause were significantly more likely to have higher levels of 16alfa-OH (OR=(tertile 3 vs tertile 1) 7.37, 95% Confidence Interval (CI) 2.20-24.70), but there was no type of menopause difference with respect to 2-OH tertile. In all MAMS control subjects (N=380), breast density correlated weakly with log-transformed serum concentrations of 16alfa-OH (Pearson correlation coefficient = 0.10, p-value < 0.1). Stratification according to menopausal status substantially reduced or eliminated associations between breast density and the estrogen metabolite concentrations. Logistic regression analyses showed a 3-4 fold increased risk of breast cancer among pre-menopausal women in the highest tertile of breast density compared with those in the lowest tertile of density, even with adjustment for the estrogen metabolites. A statistically non-significant 1.5-fold increased risk of breast cancer in high vs. low tertile of density was observed among post-menopausal women taking hormone therapy (HT) after adjusting for estrogen metabolites, BMI, and age. Breast density did not appear to substantially increase breast cancer risk among post-menopausal women not taking HT. CONCLUSION: In SOF, results did not show consistent associations between risk factors and estrogen metabolites except for a positive association between BMI and 16alfa-OH and surgical menopause and 16alfa-OH. With respect to MAMS, menopausal status may influence substrate estrogen hormone levels primarily, and, estrogen hormone levels may influence breast density secondarily, through pathways not involving the estrogen metabolites. The breast density-breast cancer association remains significant even with adjustment for the estrogen metabolites, at least in pre-menopausal women, suggesting that breast density may relate to breast cancer risk through pathways not involving estrogen metabolism.PUBLIC HEALTH SIGNIFICANCE: Understanding factors that affect breast density and their underlying mechanism is an important public health issue. Such an understanding will help us improve breast cancer screening and may help us identify women who are at an increased risk of breast cancer and for whom prevention strategies may be useful.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Simpson, Jennifer
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWeissfeld, Joel L
Committee MemberModugno, Francesmary
Committee MemberCauley, Jane A
Committee MemberCostantino, Joseph P
Committee MemberKkuller, Lewis
Committee MemberVogel, Victor
Date: 7 June 2006
Date Type: Completion
Defense Date: 13 March 2006
Approval Date: 7 June 2006
Submission Date: 12 April 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Epidemiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Estrogen metabolism; Breast cancer; Mammographic density
Other ID:, etd-04122006-212628
Date Deposited: 10 Nov 2011 19:36
Last Modified: 15 Nov 2016 13:39


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