Association Of Hormone Replacement Therapy Research Articles

Hormone replacement therapy and myocardial infarction and stroke in postmenopausal Korean women

Objective This study aimed to investigate the association of hormone replacement therapy (HRT) use, type, duration and age of commencement with myocardial infarction (MI) and stroke in postmenopausal Korean women. Methods This nested case–control study used data from the National Health Insurance Service database to analyze 2017 data from women aged ≥50 years and diagnosed with natural menopause between 2004 and 2007. Among 356,160 eligible women, 36,446 used HRT for ≥1 year and 319,714 did not (controls). These two groups were matched 1:1 for statistical analysis. Type and duration were categorized into three categories. Results Women who started estrogen–progestogen therapy (EPT) or estrogen therapy (ET) in their 50s, or EPT or tibolone in their ≥60s exhibited a lower stroke risk than controls. MI risk was lower among women who used tibolone – regardless of duration – or EPT or ET for 1–3 years than among controls. Stroke risk was lower with tibolone use for ≥5 years or with EPT or ET use for 1–3 years or ≥5 years than non-users. Conclusion Our study may support the beneficial effect of HRT by showing that Korean postmenopausal women who used HRT at a relatively younger and healthier age had a relative benefit for MI and stroke.

Association of hormone replacement therapy and the risk of knee osteoarthritis: A meta-analysis.

The relationship between hormone replacement therapy (HRT) and osteoarthritis is controversial in epidemiological studies. With the aim of better understanding the effect of HRT use, this first meta-analysis was implemented to explore the association of HRT and knee OA. A series of data is retrieved from Web of Science, PubMed, and Embase databases to observe the association of HRT and knee osteoarthritis up to December 2021. Two separated reviewers chose the research, extracted the data, and evaluated the study quality. Pooled estimates of 95% CI and HRs were acquired through a random-effects model. Finally, there existed 13 pieces of research, containing one case-control research, four cross-sectional pieces of research, as well as eight cohort pieces of research, involving 2573,164 participants. The overall results showed that the use of HRT was related to a raised risk of knee OA (HR = 1.24, 95% CI 1.07-1.45). And the pooled analysis showed a statistically significant raised risk of knee joint replacement (HR = 1.30, 95% CI 1.09-1.54) when using HRT. In addition, the outcome exhibits the raised knee OA risk for the present users of HRT (HR = 1.40, 95% CI 1.16-1.68) according to HRT status. In the past users of HRT, the augment of knee OA risk was not statistically evident (HR = 1.16, 95% CI 0.94-1.42). We observed that HRT use was related to a raised knee OA risk. Furthermore, future studies might focus on relevant mechanistic to verify our observed associations.

Association of hormone replacement therapy with risk of gastric cancer: a systematic review and meta-analysis

Hormone replacement therapy (HRT) is widely used to relieve menopausal symptoms; however, it remains unclear whether the use of HRT was associated with gastric cancer. We conducted a systematic review and meta-analysis to synthesize available evidence. This study followed the PRISMA guideline to report meta-analysis. PubMed, Embase, and Cochrane library were searched from conception through 23 February 2022. Eligible studies reporting risk of gastric cancer after HRT were screened and accessed by two independent reviewers. Random-effects meta-analysis was used to calculate pooled risk estimate as relative risk (RR, 95% CI). Pre-established review protocol was registered in PROSPERO (CRD42021281260). Among the 1095 articles identified, we included 11 studies with 1,919,089 women in this meta-analysis. The combined risk estimate (RR, 0.72; 95% CI 0.64–0.81; I2 = 2%) indicated that the use of HRT was associated with a 28% reduction in risk of gastric cancer compared with those who had no HRT exposure. The narrow prediction interval (0.62–0.84) for gastric cancer risk suggested a low between-study variance. In subgroup analysis defined by HRT formulation, there were reduction in risks of gastric cancer after the use of estrogen-only therapy (Pooled RR, 0.63; 95% CI 0.51–0.77, I2 = 0%) and estrogen-progestin therapy (Pooled RR, 0.70; 95% CI 0.57–0.87; I2 = 0%), as compared with non-users. In this systematic review and meta-analysis, the use of HRT was associated with a reduced gastric cancer risk regardless of HRT formulation. Further investigations are warranted to confirm underlying mechanisms.

The Contribution of Hormone Replacement Therapy in Postmenopausal Women to Prevent Periodontal Disease

Aim: We investigated the possible association of hormone replacement therapy (HRT) administration and periodontitis in postmenopausal women by testing of systematic inflammatory parameters. Participants and Methods: 169 postmenopausal women participated in a prospective clinical study. They were divided into two groups: Group HRT (n=69) received HRT and Group no-HRT (n=100) did not receive HRT, but continued with body exercise and daily suitable natural food diet. We measured in the serum: Interleukin-1a (IL-1a); Interleukin-1b (IL-1b); Interleukin-6 (IL-6); Τumor necrosis factor (TNF-α); C-reactive protein of serum (CRP); Alkaline phosphatase (ALP); and Activin A. We also examined: oropharyngeal cavity microbial cultures; use of periodontal probe; depth of pocket; and bone mineral density. Results: The laboratory analyses showed statistical significant decrease of TNF-a (p<0.001), IL-6 (p<0.001), IL-1a (p<0.001), IL-1b (p<0.001), alkaline phosphatase (p<0.001) and CRP (p<0.001) in Group HRT compared to no-HRT. Activin A was also reduced but not statistically significantly (p=0.549). Oropharyngeal cavity cultures were all negative in Group HRT. Conclusion: We conclude that post-menopausal women after administration of HRT are protected of oral cavity health problems periodontitis and other local symptoms,

Association of hormone replacement therapy with mortality in colorectal cancer survivor: a systematic review and meta-analysis

BackgroundHormone replacement therapy (HRT) use has shown to be associated with a reduced risk of colorectal cancer, however, its impact on survival among women with colorectal cancer remains uncertain. This meta-analysis aimed to systematically assess the survival benefit of HRT use in patients with colorectal cancer.MethodsPRISMA guidelines for the reporting of meta-analyses were followed. We systematically searched PubMed, Embase, Cochrane library, Scopus, and PsycINFO from inception to 12 January 2019, with no language restrictions, for randomized controlled trials and cohort studies reporting the association between hormone replacement therapy and risk of colorectal cancer mortality or all-cause mortality in colorectal cancer survivors. We used the Newcastle-Ottawa Scale to assess the risk of bias of the included studies. We summarized the association as hazard ratio (HR; 95% CI) using random-effects meta-analysis. The study protocol was registered in PROSPERO (CRD42017071914).ResultsOf 1648 articles identified, five cohorts including 10,013 colorectal cancer survivors were included in this meta-analysis. Compared with women with no prior use of HRT, those reporting current use of HRT had lower risks of colorectal cancer-specific mortality (HR, 0.71 [95% CI, 0.62–0.80], I2 = 0%) and overall mortality (HR, 0.74 [95% CI, 0.67–0.81], I2 = 0%). Low between-study variance was also suggested by the narrow prediction interval for colorectal cancer-specific mortality (0.58–0.86) and overall mortality (0.63–0.87), which indicated that a future study will show survival benefits in women with current HRT use compared with those with no HRT exposure. Inverse associations with colorectal cancer-specific (HR, 1.02 [95% CI, 0.82–1.28], I2 = 0%) and overall mortality (HR, 1.07 [95% CI, 0.90–1.27], I2 = 0%) were not observed for former users of HRT. Sensitivity analyses revealed no differences in the risk estimates between two groups.ConclusionsThe findings suggest that the current use of HRT is associated with lower risks of colorectal cancer-specific and overall mortality in patients with colorectal cancer. Further investigations to elucidate the underlying mechanism are warranted.

Association of hormone replacement therapy with increased risk of meningioma in women: A hospital-based multicenter study with propensity score matching.

There is no consensus regarding the association between hormone replacement therapy (HRT) and risk of meningioma so far. We conducted the first study among Chinese female patients to investigate the influence of HRT use on the risk of meningioma. We retrospectively collected records of diagnosis of meningioma for women aged 50 years and above during 2011-2016 and dispense of HRT prior to meningioma diagnosis in three tertiary hospitals in China. Meningioma cases were matched with controls at a ratio of 1:2 by using nearest neighbor propensity scores matching in order to balance the baseline characteristics between groups, which generated a total of 629 cases with 1258 controls. We observed prior use of HRT associated with increased risk of meningioma (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.4) and the association was more prominent among women having multiple HRT dispenses and longer term exposure (OR, 1.3; 95% CI, 1.1-1.6), among those with combination therapy of estrogens and progestogens (OR, 1.3; 95% CI, 1.1-1.7) than monotherapy, and among progestogen users than estrogen users as for monotherapy. Furthermore, vaginal, subcutaneous implant seems to be associated with a higher risk of meningioma compared with oral administration although no significance had been reached. This case-control study provides evidence that hormone use for an HRT purpose might constitute the development and growth of meningioma as an independent risk factor, especially for combination therapy and/or long-term users, which supports that meningioma might be a hormone-sensitive tumor.

Association of postmenopausal hormone replacement therapy on metabolic syndrome components among diabetic and nondiabetic women

Introduction It has been reported that high prevalence of metabolic syndrome and increased risk of diabetes in postmenopausal women. This may be hormone imbalance caused by ovarian failure in menopause periods. Although many studies have reported the effect of hormone replacement therapy (HRT) on chronic diseases, the risk and benefits of HRT are still controversial. Most of studies are focused on older white women, and studies target for younger menopausal Asian women are insufficient. In this study, we investigated the effect of HRT on metabolic syndrome components according to diabetes status in Korean women. Methods This study was conducted in the Health Examinees (HEXA) study, a multicenter-based cohort using baseline data from 2004 to 2013. A total of 47,307 nondiabetic and 4003 diabetic postmenopausal women aged 40–69 years were included after excluding participants without information of menopause status, HRT and diabetes. Data was collected using interviewer-administered self-reported questionnaires. HRT was categorized into never, past and current users. Diabetes was defined as fasting glucose level ≥ 126 or reported medication use (hyperglycemic drug or insulin) by considering diagnosis of diabetes at recruitment. The mean differences of metabolic syndrome components[fasting glucose (FG), total cholesterol, high-density lipoprotein (HDL), triglyceride (TG), systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), waist circumstance (WC), waist-hip ratio (WHR) and visceral fat] were assessed by using a general linear model (GLM) and Tukey's multiple comparisons tests by adjusting for age, education, smoking, drinking, physical activity, hypertension, dyslipidemia and family history of diabetes or hypertension. The associations of HRT on metabolic syndrome components were performed stratified by diabetes status and the duration and the period of initiation of HRT after the menopause were considered among current users. Results HRT use was associated with lower FG, total cholesterol, TG, SBP, DBP, BMI, WC, WHR and visceral fat among nondiabetic women, which were more stronger among current HRT users; mean differences for FG (past vs. never: 0.43 [95% CI: 0.16, 0.69] and current vs. never: 2.98 [95% CI: 2.57, 3.39]), total cholesterol (past vs. never: −0.08 [95% CI: −0.96, 0.81] and current vs. never: 11.39 [95% CI: 10.02, 12.76]), TG (past vs. never: 2.13 [95% CI: 0.16, 4.10] and current vs. never: 12.30 [9.26, 15.33]), WC (past vs. never: 0.77 [95% CI: 0.56, 0.97] and current vs. never: 1.26 [95% CI: 0.94, 1.57]), and visceral fat (past vs. never: 0.06 [95% CI: 0.04, 0.09] and current vs. never: 0.11 [95% CI: 0.07, 0.16]). The associations of HRT use on FG, total cholesterol, TG, SBP and WC were still significant among diabetic women. Considering the duration and the period of initiation of HRT after the menopause among current users, we could not confirm the differential associations between the groups, though. Conclusion Healthy postmenopausal women could be expected to reduce of metabolic syndrome components by using HRT. It is still necessary to further study to evaluate the risks and benefits of HRT applied for younger healthy menopausal women.

Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast Cancer Cell Growth

ABSTRACTDue to the association of hormone replacement therapy (HRT) with breast cancer risk, estrogenically active soy isoflavones are considered as an HRT alternative to alleviate menopausal symptoms. However, several recent reports challenged the health benefits of soy isoflavones and associated them with breast cancer promotion. While glyconic isoflavones are the major constituents of soybean seeds, due to their low cell permeability, they are considered to be biologically inactive. The glyconic isoflavones may exert their effects on membrane-bound estrogen receptors or could be converted to aglycones by extracellular β-glucosidases. Therefore, we hypothesized that despite their low cell permeability, soybean cultivars with high glyconic isoflavones may promote breast cancer cell growth. To test this, composition and estrogenic activity of isoflavones from 54 commercial soybean cultivars were determined. Soybean seeds produced in identical climate and growth conditions were used to minimize the effects of extraneous factors on isoflavone profile and concentrations. The glyconic daidzin concentration negatively correlated with genistin and with other aglycones. Relative to control, isoflavone extracts from 51 cultivars were estrogenic and promoted the growth of estrogen receptor positive (ER+) breast cancer cell line MCF-7 from 1.14 to 4.59 folds and other three cultivars slightly reduced the growth. Among these, extracts from three cultivars were highly estrogenic and promoted MCF-7 cell growth by 2.59–4.64 folds (P<0.005). Among six isoflavones, daidzin was positively associated with MCF-7 cell growth (P<0.005, r = 0.13966), whereas the negative correlation between genistin and MCF-7 cell growth was nearly significant (P≤0.0562, r = −0.026141). Furthermore, in drug interaction studies daidzin-rich isoflavone extracts antagonized tamoxifen, an ER inhibitor. Taken together, our results suggest that the glyconic daidzin-rich soy isoflavone extracts may exert estrogenic effects and promote ER+ breast cancer growth.

Associations of hormone replacement therapy and oral contraceptives with risk of colorectal cancer defined by clinicopathological factors, beta-catenin alterations, expression of cyclin D1, p53, and microsatellite-instability.

BackgroundPostmenopausal hormone therapy (HRT) and oral contraceptive (OC) use have in several studies been reported to be associated with a decreased colorectal cancer (CRC) risk. However, data on the association between HRT and OC and risk of different clinicopathological and molecular subsets of CRC are lacking. The aim of this molecular pathological epidemiology study was therefore to evaluate the associations between HRT and OC use and risk of specific CRC subgroups, overall and by tumour site.MethodIn the population-based prospective cohort study Mamö Diet and Cancer, including 17035 women, 304 cases of CRC were diagnosed up until 31 December 2008. Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status had previously been assessed in tissue microarrays with tumours from 280 cases. HRT was assessed as current use of combined HRT (CHRT) or unopposed oestrogen (ERT), and analysed among 12583 peri-and postmenopausal women. OC use was assessed as ever vs never use among all women in the cohort. A multivariate Cox regression model was applied to determine hazard ratios for risk of CRC, overall and according to molecular subgroups, in relation to HRT and OC use.ResultsThere was no significantly reduced risk of CRC by CHRT or ERT use, however a reduced risk of T-stage 1–2 tumours was seen among CHRT users (HR: 0.24; 95% CI: 0.09-0.77).Analysis stratified by tumour location revealed a reduced overall risk of rectal, but not colon, cancer among CHRT and ERT users, including T stage 1–2, lymph node negative, distant metastasis-free, cyclin D1 - and p53 negative tumours.In unadjusted analysis, OC use was significantly associated with a reduced overall risk of CRC (HR: 0.56; 95% CI: 0.44-0.71), but this significance was not retained in adjusted analysis (HR: 1.05: 95% CI: 0.80-1.37). A similar risk reduction was seen for the majority of clinicopathological and molecular subgroups.ConclusionOur findings provide information on the relationship between use of HRT and OC and risk of clinicopathological and molecular subsets of CRC.

Interactions of Hormone Replacement Therapy, Body Weight, and Bilateral Oophorectomy in Breast Cancer Risk

To examine potential modifying effects of body weight and bilateral oophorectomy on the association of hormone replacement therapy (HRT) with risk of breast cancer, overall and by subtypes according to status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) among postmenopausal women. This analysis included 2,510 postmenopausal white women recruited in the Nashville Breast Health Study, a population-based case-control study of breast cancer. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) for associations between HRT use and risk of breast cancer overall and by subtypes, adjusted for age and education. Among women with natural menopause and body mass index (BMI) < 25 kg/m(2), ever-use of HRT was associated with increased breast cancer risk (OR, 1.95; 95% CI, 1.32-2.88). Risk was elevated with duration of HRT use (P for trend = 0.002). Similar association patterns were found for ER(+), ER(+)PR(+), and luminal A cancer subtypes but not ER(-), ER(-)PR(-), and triple-negative cancer. In contrast, ever-HRT use in overweight women (BMI ≥ 25 kg/m(2)) showed no association with risk of breast cancer overall or by subtypes; interaction tests for modifying effect of BMI were statistically significant. Ever-HRT use was associated with decreased breast cancer risk (OR, 0.70; 95% CI, 0.38-1.31) among women with prior bilateral oophorectomy but elevated risk (OR, 1.45; 95% CI, 0.92-2.29) among those with hysterectomy without bilateral oophorectomy (P for interaction = 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ER(+) and luminal A only. Body weight and bilateral oophorectomy modify associations between HRT use and breast cancer risk, especially the risk of hormone receptor-positive tumors.

The Effects of Postmenopausal Hormone Use on Cataract: A Meta-Analysis

BackgroundCataract is the leading cause of blindness worldwide. Many observational studies assessed the relationship between postmenopausal hormone replacement therapy (HRT) and risk of cataract development, but the reported results were controversial. The aim of present meta-analysis was to evaluate the association of postmenopausal hormone replacement therapy with risk of cataract development.MethodsThe eligible observational studies, including cross-sectional, case–control and cohort studies, were identified by searching PubMed and Embase during March of 2013. Either a fixed- or a random-effects model was used to calculate the pooled odds ratio (OR) with its 95% confidence interval (95%CI). Subgroup analysis on cataract types was performed.ResultsA total of four cohort and five case-control or cross-sectional studies were finally included into this meta-analysis. Overall, a significant decreased risk of developing any type of cataract was found in ever HRT group as compared with non-HRT group among cohort studies (OR 0.83; 95%CI: 0.71,0.97) and case-control or cross-sectional studies (OR 0.74; 95%CI: 0.59,0.93). Subgroup analysis on cataract types determined that the significantly decreased risk of nuclear cataract in current HRT group (OR 0.72; 95%CI: 0.61,0.85) and also a critically reduced risk of nuclear cataract in ever HRT group (OR 0.80; 95% CI: 0.64,1.01) were found among case-control or cross-sectional studies, as compared with non-HRT group. No association of HRT with risk of cortical and posterior subcapsular cataract was observed.ConclusionsThe results of present meta-analysis indicate that postmenopausal hormone use may play a protective role in cataract development.

NONALCOHOLIC FATTY LIVER DISEASE IN MENOPAUSAL WOMEN

Nonalcoholic Fatty Liver Disease (NAFLD) is common in postmenopausal women. It is associated with metabolic syndrome. However, the influence of hormone replacement therapy in NAFLD development in these women needs to be investigated. This study aimed to describe the clinical characteristics of NAFLD in postmenopausal women, and the relationship between hormone replacement therapy and this disease. From April 2009 to April 2011, 292 postmenopausal women from National Health System from Northeast of Brazil were selected, and 251 were included in this study. Menopause was defined as the absence of menstruation for 12 consecutive months in otherwise healthy women. Criteria to NAFLD included: presence of steatosis on abdominal ultrasound; history of alcohol consumption less than 20 g/day and exclusion of other liver diseases. All women underwent a clinical evaluation. Standard univariate and multivariate analyses were performed to evaluate the results. The mean age was 56.5 ± 6.7 years. Hormone replacement therapy was referred by 21.1% (53) women and 78.9% (198) was not. Prevalence of NAFLD was 37.1% (93/251) in postmenopausal women, 26,4% (14/53) in the group with hormone replacement therapy and 39,9% (79/198) without hormone replacement therapy. Gamma-glutamyl transpeptidase (P = 0.001), alanine transaminase (P<0.01), ferritin (P<0.001) and insulin resistance (homeostatic model assessment of insulin resistance ≥3) (P<0.001) were higher in the group of women with NAFLD diagnosis who did not referred the use of hormone replacement therapy. Metabolic syndrome was also more frequent in women with NAFLD, who did not refer hormone replacement therapy. In conclusion this data suggests elevated prevalence of NAFLD in postmenopausal women; negative association of hormone replacement therapy and NAFLD.

Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study

IntroductionAssociations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use.MethodsWithin the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed.ResultsFor risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime.ConclusionsAn elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

Abstract P6-09-03: No Increased Breast Cancer Risk with Hormone Replacement Therapy (HRT) in Women with Benign Breast Disease

Abstract The association between hormone replacement therapy (HRT) and breast cancer risk in women with benign breast disease (BBD) is unclear. However, others have shown that HRT use is associated with the development of proliferative breast disease (Rohan et. al, CEBP 2008). To better clarify potential risks associated with postmenopausal hormone use in women with BBD, we performed a nested case control study within the Mayo Clinic Benign Breast Disease Cohort. In the cohort, there are 11,079 women who had benign breast biopsies between 1967 and 1996 and for whom we have outcome and risk factor data, including use of HRT. We studied 947 cases (breast cancer after BBD) and two controls matched to each case based on age and year of BBD. Information on use of HRT was obtained through use of questionnaires and medical record review with a mean time of follow up of 17.4 years. HRT use, histology, involution status, and family history were all evaluated for impact on breast cancer risk in a multivariate model. As shown in Table 1, when looking at effects of histology, involution, and family history, we confirmed previously reported findings of risk (Hartmann LC et. al, NEJM 2005). Specifically, we saw increased risk in women with AH vs. PDWA or NP, decreased risk with complete involution vs. partial or no involution, and increased risk with strong family history vs. weak or no family history. Associations of hormone replacement therapy and other relevant clinical variables with risk of breast cancer Multivariate model simultaneously including all variables listed in the table. HRT=hormone replacement therapy. NP=non-proliferative. PDWA=proliferative disease without atypia. AH=atypical hyperplasia We found that women who had used HRT had no higher risk of developing breast cancer than women who had not used HRT. Specifically, with Never Users as the reference group, those with 5 years or less exposure had OR 0.80 (0.56-1.15); 6-10 years, 0.85 (0.56-1.28) and 11+ years, 0.51 (0.36-0.72), p =0.002. In conclusion, we found that HRT use among postmenopausal women with BBD was not associated with an increased risk of breast cancer. In this case-control set, we confirmed previous findings regarding well established risk factors of histology, involution status, and family history. While HRT use may contribute to the development of proliferative breast disease, we do not see that HRT is associated with additional breast cancer risk, beyond that of the proliferative disease itself. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-03.

Abstract P6-09-09: Dual Estrogen Effects on Breast Cancer: Endogenous Estrogen Stimulates, Exogenous Estrogen Protects. Further Investigation of Estrogen Chemoprevention Is Warranted

Abstract Introduction Until the randomized Women Healths Initiative [WHI] trials 1,2, most hormone replacement therapy (HRT) studies showed an association of HRT with higher BrCa risk. However, our recent reviews of the WHI trials suggested that Estrogen alone can be protective while HRT based on Estrogen + Progestin can be carcinogenic 3, 4. In this analysis, we expand this concept to examine the difference between “Exogenous” Estrogen — delivered as part of HRT, versus “Endogenous” Estrogen — i.e. E produced by human tissues. Rationale 1: Endogenous E is carcinogenic. Reducing E levels through oophorectomy, selective oestrogen receptor modulators (SERMs) or with aromatase inhibition is effective at all stages of oestrogen receptor positive breast cancer and is significantly protective against BrCa in high risk women 5. Rationale 2: Exogenous E Protective: Updates of the WHI trial 2 [women with hysterectomy, randomized to E alone versus Placebo, 1,2 ] with analyses according to prior history of Benign Breast Disease (PH BrD); a first degree relative with BrCa (PH 1st Rel BrCa); or prior HRT use, show: Results of the WHI trial 2 CONCLUSIONS These data are compatible with a dual estrogen effect where Exogenous Estrogen is protective, in contrast to the carcinogenic impact of Endogenous Estrogen. The protective effect of Estrogen is comparable in magnitude to that reported with tamoxifen in high risk women. Based on these data, we propose that: 1. In selected women - [i.e. the majority of the WHI HRT trial 2 participants, 71.5 - 80%] - the use of HRT based on Estrogens alone may be appropriate to manage menopausal symptoms, as it is associated with a significant reduction of BrCa rates. 2. The use of Exogenous Estrogen in chemoprevention merits validation, with the optimum Estrogen regimen determination [type of Estrogens; dose; mode of delivery, etc.] high priority.

Effect Modification by Catalase Genotype Suggests a Role for Oxidative Stress in the Association of Hormone Replacement Therapy with Postmenopausal Breast Cancer Risk

Catalase, a ubiquitous heme enzyme, catalyzes conversion of hydrogen peroxide to water and molecular oxygen, protecting cells from oxidative stress. A C/T polymorphism in the promoter region of the CAT gene (rs1001179) affects transcriptional activity and RBC catalase levels. Oxidative stress may explain the observed increased postmenopausal breast cancer risk associated with hormone replacement therapy (HRT). We examined CAT genotype, HRT, and postmenopausal breast cancer risk in the Western New York Exposures and Breast Cancer case-control study. Cases (n = 616) were women with primary, incident, pathologically confirmed breast cancer. Randomly selected controls (n = 1,082) were frequency matched to cases on age and race. Genotype was assayed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for potential confounders. CAT genotype alone was not associated with breast cancer risk. Ever use of HRT was associated with increased risk (OR, 1.39; 95% CI, 1.11-1.75). The increase with ever use was more pronounced among those with variant CT or TT CAT genotype (OR, 1.88; 95% CI, 1.29-2.75) than among those with CC (OR, 1.15; 95% CI, 0.86-1.54). Similarly, risk associated with >or=5 years of HRT use was greater among those with at least one variant T allele (OR, 2.32; 95% CI, 1.50-3.59). Increased risk was limited to estrogen receptor-positive tumors. Our findings suggest that CAT genotype modifies the effect of HRT use on breast cancer risk and that HRT may affect risk by affecting oxidative stress.

The hormone replacement therapy opposed to low dose tamoxifen (HOT) study: safety data from an ongoing phase III trial

1514 Background: Primary prevention trials have shown that tamoxifen (T) lowers ER+ breast cancer (BC) incidence by 48%. While the IBIS I update showed mixed findings, the Italian trial showed an interesting positive risk/benefit ratio in T and hormone replacement therapy (HRT) users: fewer BC, endometrial cancer comparable to placebo, and no cardiovascular diseases (CVD) excess. In a phase II study, low dose T and HRT showed a safe gynecological profile and did not increase menopausal symptoms. Moreover low dose T maintains the same antiproliferative effects as the standard dose. To improve BC prevention and quality of life (QoL) in menopausal women we started a multicentric, phase III trial of low dose T in HRT users. Methods: current or de novo HRT users are randomized to T 5 mg/day or placebo for 5 yrs. The primary aim is the reduction of invasive or in situ BC. Secondary aims are: safety, gene polymorphisms (SNPs) correlated to BC risk and T activity. In a subgroup transvaginal ultrasound (TvUS) and endometrial biopsy is being performed after 3 years of treatment to monitor endometrial effects. Results: as of December 31 2006, 1870 women were enrolled, of which 21% were hysterectomized. Median age is 53 years (33–72), BMI is &lt;25 in 66%, =25&lt;30 in 26%, &gt;30 in 8%. Current or de novo users are 80% and 20%. 84% participants have at least one follow-up visit. 128 subjects performed already the 3 years TvUS and endometrial biopsy: so far no atypical hyperplasia or cancer was found. A modest increase of menopausal symptoms was observed (hot flashes 42% vs 52%, night sweating 39% vs 44%). Drop-outs are 23%, of which 13% due to AE including: 21 cancers (12 invasive BC, 1 DCIS), 13 CVD (3 VTE), 9 gynecological (5 endometrial polyps). Conclusions: combination of low dose T and HRT has reasonable safety profile, we have reached almost 1,900 women on study and AE rate is very low. These unblinded findings support the safety of the association of HRT and T. No significant financial relationships to disclose.

Hormone replacement therapy and risk for coronary heart disease: Data from the CORA-study—A case-control study on women with incident coronary heart disease

Background Hormone replacement therapy (HRT) has been suggested to prevent cardiovascular disease, while some intervention studies have shed doubt on this concept. Thus, uncertainty remains whether current HRT use is beneficial as to cardiovascular disease or may even be harmful. Objectives This research investigates the association of hormone replacement therapy, risk factors and lifestyle characteristics with the manifestation of coronary heart disease in current HRT users versus never users. Design The coronary risk factors for atherosclerosis in women study (CORA-study) provide clinical and biochemical parameters and data on lifestyle in 200 consecutive pre- and postmenopausal women with incident coronary heart disease compared to 255 age-matched population-based controls, of which 87.9% were postmenopausal. Results Significantly more controls than cases used currently HRT for a median of 9.5 years (32.9% versus 20.2%), while 50.0% of cases and 42.5% of controls had never used HRT ( p < 0.02). Compared to women who never used HRT, current users ate less meat and sausage, had a significantly lower BMI and waist-to-hip ratio and a lower prevalence of hypertension, insulin resistance and diabetes. However, current users among cases were often smokers and smoked significantly more cigarettes than never users. In a multivariate analysis the risk of current HRT users for coronary artery disease was 57% lower than the risk of never users (odds ratio 0.428, CI 0.206–0.860, p < 0.02). Adjustment for conventional and dietary risk factors revealed neither current HRT use, nor HRT use combined with smoking as independent risk factors. Conclusions These data from the CORA-study are not compatible with an adverse impact of hormone replacement therapy on cardiovascular disease, rather support the notion of beneficial effects of HRT on weight, central adiposity, insulin sensitivity and blood pressure. Yet, the data do not support the presumption of a general healthy user effect in women on HRT either. Rather, in some women adverse lifestyle habits, especially intense smoking, appear to counteract possible beneficial effects of HRT.

P3-144: Association of hormone replacement therapy and cognitive impairment: Evidence of confounding by demographics and serum α-tocopherol status

Studies of hormone replacement therapy (HRT) and cognitive function in older women have varied from beneficial to possibly detrimental. Some studies have suggested that cognitive effects of HRT may differ by age at HRT initiation, or interact with other cognitive risk factors. Cognitive testing methodology has differed between studies, and observational studies have not always had data on relevant potential confounders. This analysis of data from an observational ancillary study to the Women's Health Initiative (WHI) examines whether HRT use is associated with cognitive impairments of memory or mixed–domain type, determined by a neuropsychological test battery. Study subjects were 523 women age 60 years and over at time of cognitive testing. Estrogen use history (“never” (N=243), “past” (N=140) or “current” (N=140)) was determined from previous WHI data and updated at cognitive test visit. Memory impairment was considered present if women scored at least 2 sd below age and education–specific norms for one or more tests of memory. Mixed domain impairment was defined as scoring below norms on one or more tests in two or more domains (memory, executive function, language, attention, and visual function). In unadjusted analyses, neither current (OR 1.1 95% CI 0.7–1.7) nor past (0.6 95% CI 0.3–1.0) HRT use was associated with memory impairment. Reduced odds of mixed–domain impairment were seen for past HRT users (0.3; 0.1–0.7) but not current users (0.7; 0.4–1.3). Among ever–users, no association was seen between mixed domain impairment and age at first use (p=.58) or use of progestins (p=.23). Adjusting for previously–identified covariates (age, education, race/ethnicity, and lowest quartile serum α–tocopherol), the association of past HRT use with mixed impairment was no longer statistically significant (OR 0.5; 0.2–1.1). Adjusting additionally for Apo e4 or cardiovascular disease did not affect these results. No evidence of interactive effects was seen between HRT use and age, serum α–tocopherol, or e4. No association was seen between current HRT use and memory or mixed–domain impairments. Confounding by age, education, race/ethnicity, and serum tocopherol status appeared to account for the bivariate association between past HRT use and mixed domain cognitive impairment.

Association of Serum Proinsulin With Hormone Replacement Therapy in Nondiabetic Older Women

One putative benefit of hormone replacement therapy (HRT) is a reduced risk of diabetes or reduced fasting glucose level. We report here the association of HRT with proinsulin, insulin, and fasting and postchallenge glucose levels in older adults. Current HRT use was validated and cross-sectionally compared with diabetes-related variables in 785 women without diabetes by history or glucose tolerance test. Median age was 72 years (range 50-97); median value of fasting plasma glucose, postchallenge plasma glucose, and proinsulin was 5.08 mmol/l, 6.93 mmol/l, and 9.3 pmol/l, respectively. In age-adjusted comparisons, current HRT use was associated with significantly lower fasting plasma glucose and higher postchallenge plasma glucose compared with never/previous HRT use, as well as with lower LDL and higher HDL cholesterol and higher triglycerides. Fasting and postchallenge intact insulin did not differ by HRT group, but proinsulin was significantly lower in current HRT users than in previous and never HRT users. The significant association between proinsulin and HRT status persisted after adjustment for age, waist-to-hip ratio, pulse pressure, LDL-to-HDL cholesterol ratio, triglycerides, fasting and postchallenge glucose, and intact insulin. Reduced fasting and increased 2-h glucose replicate findings in a randomized clinical trial. The proinsulin effect has not been previously reported. Decreased fasting glucose and proinsulin levels in current HRT use suggest a potential antidiabetes effect of HRT. Increased postchallenge glucose in HRT, however, suggests insulin resistance and would be expected to increase the risk of heart disease.