Cumulative Estrogen Exposure Research Articles

Lifetime Cumulative Effect of Reproductive Factors on Stroke and Its Subtypes in Postmenopausal Chinese Women: A Prospective Cohort Study.

Multiple reproductive factors are associated with stroke. Little is known about the cumulative effects of reproductive factors during a reproductive life course on stroke and its subtypes, especially among female Chinese individuals. The objective of this study was to assess the associations of lifetime cumulative estrogen exposure due to reproductive factors with stroke and its etiologic subtypes among postmenopausal Chinese women. Postmenopausal women without prior stroke at baseline (2004-2008) were selected from the China Kadoorie Biobank (CKB). Lifetime cumulative estrogen exposure due to reproductive factors was assessed using 3 composite indicators: reproductive lifespan (RLS), endogenous estrogen exposure (EEE), and total estrogen exposure (TEE). Stroke and its subtypes, ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), were identified through linkage to a disease registry system and health insurance data during follow-up (2004-2015). Multivariable-adjusted Cox proportional hazards regression models were applied to estimate the adjusted hazard ratio (aHR) and 95% CIs for the risk of stroke by quartiles of RLS, EEE, and TEE, respectively. A total of 122,939 postmenopausal participants aged 40-79 years without prior stroke at baseline were included. During a median follow-up period of 8.9 years, 15,139 cases with new-onset stroke were identified, including 12,853 cases with IS, 2,580 cases with ICH, and 269 cases with SAH. Compared with the lowest quartile (Q1) of RLS, the highest quartile (Q4) had a lower risk of total stroke (aHR: 0.95, 95% CI 0.92-0.98), IS (aHR: 0.95, 95% CI 0.92-0.98), and ICH (aHR: 0.87, 95% CI 0.81-0.94). Both EEE and TEE displayed a graded association with the subsequent descending risk of total stroke (aHR for Q4 vs Q1: EEE: 0.85, 95% CI 0.82-0.89; TEE: 0.87, 95% CI 0.84-0.90), IS (aHR for Q4 vs Q1: EEE: 0.86, 95% CI 0.83-0.90; TEE: 0.86, 95% CI 0.83-0.89), and ICH (EEE: 0.73, 95% CI 0.65-0.81; TEE: 0.83,95% CI 0.76-0.91), with a p for trend < 0.001 for all these associations. Individuals' cumulative estrogen exposure due to reproductive factors could potentially be a valuable indicator for risk stratification of stroke events after menopause.

A Lifecourse Perspective on Female Sex-Specific Risk Factors for Later Life Cognition.

The prevalence of Alzheimer's disease and related dementias is greater in women compared to men. We provide a review of female sex-specific risk factors across the lifecourse for cognition in older adulthood, highlighting areas that need further study. Pregnancy may affect late-life cognition, with adverse pregnancy outcomes associated with an increased risk of cognitive decline but parity providing a protective effect. Cumulative estrogen exposure, influenced by age of menarche, menopause, and exogenous estrogen use, may modify a woman's risk for dementia. Menopause transition-associated symptoms may impact cognitive health at the time of the symptoms, but long-term effects remain unknown. As compared to natural menopause, surgical menopause seems to increase the risk for cognitive impairment. Studies that have assessed the association between women's reproductive health and cognition have produced conflicting results. Future studies that address these inconsistencies among diverse populations are needed to better care for women throughout their lives.

The Effects of Lifetime Estrogen Exposure on Breast Epigenetic Age.

Estrogens are thought to contribute to breast cancer risk through cell cycling and accelerated breast aging. We hypothesize that lifetime estrogen exposure drives early epigenetic breast aging observed in healthy women. In this study, we examined associations between hormonal factors and epigenetic aging measures in healthy breast tissues. We extracted DNA from breast tissue specimens from 192 healthy female donors to the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Methylation experiments were performed using the Illumina EPIC 850K array platform. Age-adjusted regression models were used to examine for associations between factors related to estrogen exposure and five DNA methylation-based estimates: Grim age, pan-tissue age, Hannum age, phenotypic age, and skin and blood clock age. Women were aged 19-90 years, with 95 premenopausal, and 97 nulliparous women. The age difference (Grim age - chronologic age) was higher at earlier ages close to menarche. We found significant associations between earlier age at menarche and age-adjusted accelerations according to the Grim clock, the skin and blood clock, and between higher body mass index (BMI) and age-adjusted accelerations in the Grim clock, Hannum clock, phenotypic clock, and skin and blood clock. Earlier age at menarche and higher BMI are associated with elevations in DNA methylation-based age estimates in healthy breast tissues, suggesting that cumulative estrogen exposure drives breast epigenetic aging. Epigenetic clock measures may help advance inquiry into the relationship between accelerated breast tissue aging and an elevated incidence of breast cancer in younger women.

Association of Sjögren's Syndrome With Reduced Lifetime Sex Hormone Exposure: A Case-Control Study.

To test whether cumulative estrogen exposure, as determined by age at menarche, age at menopause, female hormone use, hysterectomy, and parity, have an effect on the development of primary Sjögren's syndrome (SS). We performed a case-control study of 2,680 women from the Sjögren's International Collaborative Clinical Alliance registry, including 1,320 registrants with primary SS and 1,360 with sicca symptoms but no key features of primary SS (sicca controls). The composite estrogen score (CES) was calculated by point assignment for early menarche (age ≤10 years), high parity (>3 pregnancies), hysterectomy, female hormone use, and late menopause (age ≥53 years). Cumulative menstrual cycling (CMC) was calculated as years menstruating minus time pregnant. Using a regression model that adjusted for age, recruitment site, ethnicity, education, employment status, and smoking, we observed a progressive inverse trend between primary SS and CES. The odds ratio (OR) and 95% confidence interval (95% CI) were as follows for the sicca control group: CES 1, OR 0.81 (95% CI 0.67-0.99); CES 2, OR 0.74 (95% CI 0.57-0.97); CES 3, OR 0.50 (95% CI 0.30-0.86). This trend was corroborated by analysis of CMC. At the highest level of CMC within the postmenopausal group there was a 24% reduction in cumulative sex hormone exposure among primary SS participants relative to controls. Women with primary SS have lower estrogen exposure and CMC compared to sicca controls. Increasing estrogen exposure was negatively associated with development of primary SS. Further longitudinal studies of sex hormone exposure in primary SS are needed to confirm these findings.

Abstract P1-09-08: Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women

Abstract Background: Healthy breast tissue appears older than matched peripheral blood, when using a biologic aging measurement based on DNA methylation markers. The underlying cause of this acceleration is not known. We hypothesize that cumulative estrogen exposure is associated with accelerated breast epigenetic aging. In this study, we examined factors associated with breast epigenetic age in a healthy population of women. Methods: We used breast tissue samples from 232 healthy women donors (119 pre-menopausal, 113 post-menopausal) to the Komen Tissue Bank, with data available on variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. DNA methylation experiments were performed using the Illumina EPIC 850K array platform. DNA methylation age (DNAm age) was calculated using the epigenetic clock methods developed by Horvath (2013). Total years of estrogen exposure was calculated as the difference between age at menopause (or current age) - number of live births x 9 months – number of miscarriages x 3 months. Nonparametric group testing was used to compare mean levels of the difference between DNAm age and chronologic age for pre- and post-menopausal groups. We examined the outcome “age acceleration”, calculated using the residuals of the regression of DNAm age versus chronologic age, because it is age-adjusted and independent of cell distribution. Multivariate linear regression models were used to examine for associations between age acceleration and each of our covariates. Results: Our sample included women aged 19-90 years (mean age 50.7, SD 11.8), with 114 nulliparous women. We confirmed that DNAm age in breast tissue is strongly correlated with chronologic age (ρ=0.89, p&amp;lt;0.0001). The difference between DNAm age and chronologic age is greater at earlier ages, and is significantly greater in premenopausal women (mean 8.9 years, SE 0.04), compared with postmenopausal women (mean 2.7 years, SE 0.05) (p&amp;lt;0.0001). Age acceleration was significantly associated with earlier age at menarche (β=-0.395 for each year, p=0.036). For women with limited total years of exposure to estrogen (&amp;lt;19 years), there was a significant association between age acceleration and total estrogen exposure and β=0.673 for each year, p=0.028). Conclusion: Acceleration of epigenetic age in breast tissues occurs in healthy women and is most pronounced in the pre-menopausal period. Earlier age at menarche and total years of estrogen exposure are associated with higher degree of acceleration, suggesting that cumulative estrogen exposure drives this process. Citation Format: Sehl ME, Henry JE, Storniolo AM, Horvath S, Ganz PA. Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-08.

Reproductive period and epigenetic modifications of the oxidative phosphorylation pathway in the human prefrontal cortex.

PurposeHuman females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway.MethodsUsing DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database.ResultsWe observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair.ConclusionThis study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.

Endogenous sex hormone exposure and repetitive element DNA methylation in healthy postmenopausal women.

Epigenetic mechanisms may help to explain the complex and heterogeneous relation between sex hormones and cancer. Few studies have investigated the effects of sex hormones on epigenetic markers related to cancer risk such as levels of methylation within repetitive DNA elements. Our objective was to describe the association between endogenous sex hormone exposure and levels of LINE-1 and Alu methylation in healthy postmenopausal women. We nested a cross-sectional study within the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2006). Study participants consisted of healthy postmenopausal women who had never been diagnosed with cancer (n = 289). Sex hormone exposures included serum concentrations of estradiol, estrone, testosterone, androstenedione, and sex hormone-binding globulin. We estimated the participants' lifetime number of menstrual cycles (LNMC) as a proxy for cumulative exposure to ovarian sex hormones. Buffy coat samples were assessed for DNA methylation. Linear regression was used to model the associations of interest and to control for confounding. Both estradiol and estrone had a significant positive dose-response association with LINE-1 methylation. LNMC was associated with both LINE-1 and Alu methylation. Specifically, LNMC had a non-linear "U-shaped" association with LINE-1 methylation regardless of folate intake and a negative linear association with Alu methylation, but only amongst low folate consumers. Androgen exposure was not associated with either outcome. Current and cumulative estrogen exposure was associated with repetitive element DNA methylation in a group of healthy postmenopausal women. LINE-1 and Alu methylation may be epigenetic mechanisms through which estrogen exposure impacts cancer risk.

Is estrogen exposure a protective factor for pancreatic neuroendocrine tumours in female patients with multiple endocrine neoplasia syndrome type 1?

Pancreatic neuroendocrine tumours (PNETs) are the most common cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Women have been shown to have improved survival, which may suggest a possible protective effect of female sex hormones. The aim of this study was to evaluate the relationship between estrogen exposure and PNET tumourigenesis, tumour growth and survival in female MEN1 patients with these tumours. We performed a retrospective chart review of the existing MEN1 database in our institution. Detailed information about female patients' menstrual and reproductive history, and PNET clinicopathologic characteristics was collected. Questionnaires regarding estrogen exposure were used to collect information that was missing in the database. Of 293 confirmed MEN1 cases, 141 women met the inclusion criteria. We used measures of cumulative estrogen exposure time (CEET), parity, live birth pregnancies and bilateral oophorectomy to estimate estrogen exposure. There was no significant association between CEET and time to PNET diagnosis (hazard ratio=0·966, P=0·380). For the correlation between estrogen exposure and PNET type, size, numbers, distant metastasis, lymph node metastasis, lymphovascular invasion, AJCC (American Joint Committee on Cancer) stage and overall survival, only CEET was significantly correlated with PNET size (P=0·043). In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.

The loss of estrogens in the menopause may lead to increased vulnerability for psychotic relapse, poor clinical outcome, and a need for increased antipsychotic dose. However, confounders such as cumulative estrogen exposure and time since menopause have been inadequately studied. Our aim was to investigate potential variables capable of influencing antipsychotic response in a sample of postmenopausal women with schizophrenia. Sixty-four postmenopausal schizophrenic women were followed in a 12-week prospective treatment-by-clinical requirement study. Duration of reproductive years was considered an indirect measure of lifetime cumulative estrogens exposure. Psychopathological assessment included the following: Positive and Negative Syndrome Scale, Personal and Social Performance, and Clinical Global Impression-Schizophrenia Scale. Response was defined as a reduction of 30% or more of Positive and Negative Syndrome Scale total scores. Antipsychotic adherence was assessed by plasma level monitoring at 4 weeks. Regression analyses were performed to investigate the association between potential confounding factors and antipsychotic response. Forty-two participants (66%) were found to be antipsychotic responders. Time since menopause was significantly and negatively associated with overall antipsychotic response, explaining almost 42% of the variance of the model used. Smoking and cumulative estrogen exposures were associated with improvement in negative symptoms. Smoking and time since menopause were associated with improvement in excitement symptoms, and smoking was positively associated with improvement in depressive and cognitive symptoms. Time since menopause was significantly negatively associated with antipsychotic response in postmenopausal schizophrenic women, suggesting a decline in antipsychotic response after menopause. The neurobiological basis for antipsychotic response may include a role for estrogen and nicotine receptors.

Abstract 4444: DNA methylation age is accelerated in breast tissue of healthy women donors

Abstract Background: Advanced age and cumulative estrogen exposure are well known risk factors for breast cancer. However, the mechanisms underlying the link between cellular senescence, chronic estrogen stimulation, increased cell cycling, and breast carcinogenesis are poorly understood. We examined epigenetic alterations that occur in the female breast with advancing age, and estrogen exposure. Methods: We utilized specimens from 49 women healthy tissue donors from the Komen Tissue Bank who donated both breast tissue and peripheral blood at two time points spaced at least 2 years apart. Ages of the donors ranged from 18-65 years and they were grouped by menopausal status (27 pre- and and 22 post-menopausal) and parity (21 nulliparous). We assessed epigenome-wide DNA methylation levels (Illumina 450K platform) from DNA extracted from breast and blood tissue, and calculated tissue “DNA methylation age (DNAm age)” based on methylation levels at 353 CpGs that have been shown to strongly correlate with chronologic age across tissues. We examined the relationship between this outcome and age and variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. Results: DNAm age was highly correlated with chronological age in our sample (cor = 0.8, p&amp;lt;0.001), within both peripheral blood (cor = 0.94, p&amp;lt;0.001) and breast tissues (cor = 0.88, p&amp;lt;0.001). When we examine the residuals for each sample from our regression analysis of DNAm age versus chronological age, we find that age acceleration is significantly increased in breast relative to peripheral blood tissue (p&amp;lt;0.001). In a multivariate regression analysis, we found that earlier age at menarche (β = -0.62, p = 0.04) and higher gravidity (β = 0.95, p = 0.03) were associated with higher DNAm age. Conclusions: We find that DNAm age is accelerated in breast tissue compared with peripheral blood cells in a population of healthy donors to the Komen Tissue Bank. We further note a significant association between DNAm age and early menarche, and rising number of pregnancies, suggesting that cumulative cell cycling with menstrual cycles and the tissue plasticity occurring with pregnancy may contribute to accelerated epigenetic age in the female breast. Citation Format: Mary E. Sehl, Patricia A. Ganz, Steve Horvath. DNA methylation age is accelerated in breast tissue of healthy women donors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4444.

An Association of Reaction Time with Bone Quantitative Ultrasound

Requirement of artificial bone materials is high, which demands us to consider many factors of human body. Evidence exists that estrogen influences neuronal physiology and cognitive function. Bone mineral density has been proposed as a marker for cumulative estrogen exposure. This study examined whether choice reaction time (CRT) would be related to calcaneus quantitative ultrasound (QUS). 222 ethnic Han Chinese men were recruited. Besides age and body mass index (BMI), cigarette smoking, as an important environment factor influencing cognition and bone health, was included in covariants. Results showed that CRT performance was statistically significantly positively correlated with bone quality index (p &lt; 0.01) and speed of sound (SOS) (p &lt; 0.001) before controlling covariants. After adjustment for age, BMI, and smoking, CRT remained significantly related to SOS (p &lt; 0.05). Our findings indicate that CRT may be associated with bone status, which suggests an effect of artificial bone on nervous system should be considered when it is produced.

Association of bone mineral density with breast cancer and histopathologic features of the tumor.

16 Background: High bone mineral density (BMD) has been associated with increased incidence of breast cancer. We studied the differences in BMDs between females with and without breast cancer as well as the association between BMD and the histopathological features of breast cancer. Methods: Data on BMDs and Tscores of hip and spine were collected for 311 breast cancer patients from Dexa Scans available from 5 years before or within 1 year of diagnosis. The same information was collected for 1,047 females without breast cancer (age matched with study group). The following additional data was collected for breast cancer patients: TNM staging, Histology, Estrogen receptor (ER), Progesterone receptor (PR), Ki-67 and HER-2 percentages, Tumor size, and Tumor differentiation. Results: As expected, breast cancer patients were found to have higher hip/spine BMDs than women without breast cancer (p &lt; 0.001). PR percentage was positively associated with hip BMD/Tscore and spine BMD/Tscore ([rsp=0.166/0.165, 0.145/0.164, respectively], p&lt;0.05 for all [Spearman Correlation Analysis]). Tumor size was negatively associated with spine BMD/Tscore ([rsp=-0.134, p=0.06], [rsp=-0.136, p=0.04], respectively, [Spearman Correlation Analysis]). A negative trend was seen between Ki-67 percentages and BMD (although no significance was achieved). Patients with lymphovascular invasion had lower spine Tscores than patients without lymphovascular invasion (-1.22±1.45 vs. -0.84±1.37, p=0.04, [One-way ANOVA]). Conclusions: Amongst all women studied, women with breast cancer were likely to have a higher BMD. However, higher BMD in breast cancer patients was associated with favorable tumor characteristics. Higher BMD was also associated with higher percentage of PR while no significant association was seen with ER. Greater cumulative estrogen exposure in females with higher BMD might explain these results. Estrogens are known to affect proliferation of breast cancer cells and to alter their phenotypic and cytoarchitechtural features, including enhanced induction of PR and possible downregulation of ER. Future studies are needed to explore these underlying pathways, their effect on tumor behavior, and treatment implications.

Cumulative estrogen exposure, number of menstrual cycles, and Alzheimer's risk in a cohort of British women

The effect of estrogen on Alzheimer's Disease (AD) risk has received substantial research and media attention, especially in terms of hormone replacement therapy. But reproductive history is also an important modifier of estrogenic exposure, and deserves further investigation. Importantly, there is wide variation in reproductive patterns that modifies estrogen exposure during the reproductive span, which previous AD studies have not incorporated into their calculations. We measured degree of Alzheimer's-type dementia in a cohort of elderly British women, and collected detailed reproductive and medical history information, which we used to estimate number of months with estrogen exposure and number of months with menstrual cycles. Using Cox proportional-hazards models, we find that longer duration of estrogen exposure may have a protective effect against AD risk, such that for every additional month with estrogen, women experienced on average a 0.5% decrease in AD risk (N=89, p=0.02). More menstrual cycles may also have a protective effect against AD risk, although this result was of borderline statistical significance (p<0.10). These results build upon previous methodologies by taking into account a variety of parameters including oral contraceptive use, breastfeeding, post-partum anovulation, abortions, and miscarriages. Additionally, Cox models revealed that longer reproductive span, age>21 at first birth, and more months in lifetime spent pregnant had protective effects against AD risk.

Testing the estrogen hypothesis of schizophrenia: Associations between cumulative estrogen exposure and cerebral structural measures

BackgroundBone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. MethodsDual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm2), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. ResultsFemoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: −0.019–0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001–0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000–0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. ConclusionsThe data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.

Cumulative estrogen exposure and prospective memory in older women

This study looked at cumulative lifetime estrogen exposure, as estimated with a mathematical index (Index of Cumulative Estrogen Exposure (ICEE)) that included variables (length of time on estrogen therapy, age at menarche and menopause, postmenopausal body mass index, time since menopause, nulliparity and duration of breastfeeding) known to influence estrogen levels across the life span, and performance on prospective and retrospective memory measures in a group of 50 postmenopausal women (mean age=69.3years) who, if they were current or former users of estrogen therapy, had started therapy within 5years of menopause. The ICEE was found to be a significant predictor of performance on the Prospective Memory task (F(1)=4.21, p=.046, ηp2=.084). No significant relationship was noted between the ICEE and performance on measures of retrospective memory. The results suggest that the level of cumulative lifetime exposure to estrogen a woman has influences her prospective memory performance later in life and that the influence of reproductive and biological markers of endogenous estrogen exposure are relevant factors to consider when studying the effect of estrogen therapy on cognitive functioning in postmenopausal women. In addition, the finding that performance on a measure of prospective memory, but not performance on measures of retrospective memory, was associated with the ICEE adds further support to the theory that the frontal cortex may be especially sensitive to estrogen.

Estrogen Metabolism and Exposure in a Genotypic–Phenotypic Model for Breast Cancer Risk Prediction

Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE(2)), expressed as area under the curve metric (4-OHE(2)-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE(2). We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). In the GENICA study, premenopausal women at the 90th percentile of 4-OHE(2)-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE(2)-AUC percentile (95% CI: 1.7-3.2, P = 2.9 × 10(-7)). This relative risk was 1.89 (95% CI: 1.5-2.4, P = 2.2 × 10(-8)) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3-2.6, P = 7.6 × 10(-4)), which increased to 1.83 (95% CI: 1.4-2.3, P = 9.5 × 10(-7)) when a history of proliferative breast disease was included in the model. The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates.

High bone mass as a marker for breast cancer risk.

Postmenopausal women in the highest quartile for metacarpal bone mass were found to have an increased risk of developing breast cancer, after adjusting for age and other variables known to influence breast cancer risk. Although the mechanisms responsible for this relationship have not been identified, postmenopausal bone mass may serve as an indicator of cumulative estrogen exposure.

Estrogen Exposure, Metabolism, and Enzyme Variants in a Model for Breast Cancer Risk Prediction

Estrogen is a well-known risk factor for breast cancer. Current models of breast cancer risk prediction are based on cumulative estrogen exposure but do not directly reflect mammary estrogen metabolism or address genetic variability between women in exposure to carcinogenic estrogen metabolites. We are proposing a mathematical model that forecasts breast cancer risk for a woman based on three factors: (1) estimated estrogen exposure, (2) kinetic analysis of the oxidative estrogen metabolism pathway in the breast, and (3) enzyme genotypes responsible for inherited differences in the production of carcinogenic metabolites. The model incorporates the main components of mammary estrogen metabolism, i.e. the conversion of 17beta-estradiol (E(2)) by the phase I and II enzymes cytochrome P450 (CYP) 1A1 and 1B1, catechol-O-methyltransferase (COMT), and glutathione S-transferase P1 (GSTP1) into reactive metabolites, including catechol estrogens and estrogen quinones, such as E(2)-3,4-Q which can damage DNA. Each of the four genes is genotyped and the SNP data used to derive the haplotype configuration for each subject. The model then utilizes the kinetic and genotypic data to calculate the amount of E(2)-3,4-Q carcinogen as ultimate risk factor for each woman. The proposed model extends existing models by combining the traditional "phenotypic" measures of estrogen exposure with genotypic data associated with the metabolic fate of E(2) as determined by critical phase I and II enzymes. Instead of providing a general risk estimate our model would predict the risk for each individual woman based on her age, reproductive experiences as well as her genotypic profile.

P-516: Increased end organ sensitivity to estrogen in Black women

Markers of cumulative estrogen exposure have included, bone density and endometrial thickness. It has been suggested that greater body size and perhaps increased peripheral aromatization or multiple follicle recruitment among U.S. Black women may result in higher levels of estradiol resulting in greater bone density and endometrial thickness. The objective of our study is to assess the impact of race, body composition, follicular development, and estradiol levels on bone density and endometrial thickness in areproductive aged, normo-cycling group of Black and White women.

Bone Mineral Density and the Risk of Alzheimer Disease

Some, but not all, studies have suggested that estrogen replacement therapy has a beneficial effect on cognition in postmenopausal women. Bone mineral density (BMD) is a potential surrogate marker for cumulative estrogen exposure and has been associated with cognitive performance and risk of cognitive deterioration. To examine whether low BMD in elderly individuals is associated with an increased risk of developing Alzheimer disease (AD). Community-based prospective cohort study of 987 subjects (610 women) who were cognitively intact and had baseline BMD measured at the femoral neck, the trochanter, and the radial shaft between 1988 and 1989. Incidence of AD and all-cause dementia during an 8-year follow-up period. Women in the lowest quartile of femoral neck BMD had more than twice the incidence of AD (hazard ratio, 2.04; 95% confidence interval, 1.11-3.75) and all-cause dementia (hazard ratio, 2.01; 95% confidence interval, 1.16-3.49) compared with those in higher quartiles after adjusting for age, sex, apolipoprotein E epsilon4, baseline homocysteine level, education, estrogen use, smoking, and stroke. A similar but statistically nonsignificant relationship was observed between BMD of the femoral trochanter and AD, while no such relationship was seen between radial BMD and AD or all-cause dementia. In men, there was a trend toward an inverse relationship between BMD and the risk of AD, but the relationship was not statistically significant at any of the 3 sites. Low femoral neck BMD was associated with approximately 2 times the risk of AD and all-cause dementia in women but not men, suggesting the possibility that cumulative estrogen exposure may influence the risk of developing AD. Additional studies are needed to confirm this correlation.