Use Of Postmenopausal Hormone Therapy Research Articles

Infertility and risk of postmenopausal breast cancer in the women's health initiative.

Although infertility (i.e., failure to conceive after ≥ 12months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25years of follow-up). At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

Menopausal hormone therapy use and risk of ovarian cancer by race: the ovarian cancer in women of African ancestry consortium.

Most studies examining post-menopausal menopausal hormone therapy (MHT) use and ovarian cancer risk have focused on White women and few have included Black women. We evaluated MHT use and ovarian cancer risk in Black (n = 800 cases, 1783 controls) and White women (n = 2710 cases, 8556 controls), using data from the Ovarian Cancer in Women of African Ancestry consortium. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MHT use with ovarian cancer risk, examining histotype, MHT type and duration of use. Long-term MHT use, ≥10 years, was associated with an increased ovarian cancer risk for White women (OR = 1.38, 95%CI:1.22-1.57) and the association was consistent for Black women (OR = 1.20, 95%CI:0.81-1.78, pinteraction = 0.4). For White women, the associations between long-term unopposed estrogen or estrogen plus progesterone use and ovarian cancer risk were similar; the increased risk associated with long-term MHT use was confined to high-grade serous and endometroid tumors. Based on smaller numbers for Black women, the increased ovarian cancer risk associated with long-term MHT use was apparent for unopposed estrogen use and was predominately confined to other epithelial histotypes. The association between long-term MHT use and ovarian cancer risk was consistent for Black and White women.

Association of Accelerometer-Measured Physical Activity and Sedentary Behavior With Incident Cardiovascular Disease, Myocardial Infarction, and Ischemic Stroke: The Women's Health Study.

Background Few studies have investigated associations of acclerometer-based assessments of physical activity (PA) and sedentary behavior (SB) with incidence of cardiovascular disease (CVD) and its components. This prospective cohort study assessed the associations of accelerometer-measured PA and SB with total CVD, myocardial infarction, and ischemic stroke (IS). Methods and Results The authors included 16 031 women aged 62 years and older, free of CVD, with adherent accelerometer wear (≥10 hours/day for ≥4 days) from the Women's Health Study (mean age, 71.4 years [SD, 5.6 years]). Hip-worn ActiGraph GT3X+ accelerometers measured total volume of PA (total average daily vector magnitude), minutes per day of high-light PA and moderate to vigorous PA (MVPA), and SB. Women reported diagnoses of CVD, which were adjudicated using medical records and death certificates. Hazard ratios (HRs) were estimated for each exposure, and 95% CIsusing Cox proportional hazards models were adjusted for accelerometer wear time, age, self-reported general health, postmenopausal hormone therapy, smoking status, and alcohol use. The hypothetical effect of replacing 10 minutes/day of SB or high-light PA with MVPA on CVD incidence was assessed using adjusted isotemporal substitution Cox models. Over a mean of 7.1 years (SD, 1.6 years) of follow-up, 482 total CVD cases, 107 myocardial infarction cases, and 181 IS cases were diagnosed. Compared with the lowest quartiles of total average daily vector magnitude and MVPA (≤60 minutes), women who were in the highest quartiles (>120 minutes of MVPA) had a 43% (95% CI, 24%-58%) and 38% (95% CI, 18%-54%) lower hazard of total CVD, respectively. Estimates were similar for total average daily vector magnitude and MVPA with IS, but PA was not associated with myocardial infarction overall. High-light PA was not associated with any CVD outcomes. Women who spent <7.4 hours sedentary per day had a 33% (95% CI,11%-49%) lower hazard of total CVD compared with those who spent ≥9.5 hours sedentary. Replacing 10 minutes of SB with MVPA was associated with a 4% lower incidence of total CVD (HR, 0.96 [95% CI, 0.93-0.99]). Conclusions Accelerometer-assessed total PA and MVPA were inversely associated with total CVD and IS incidence, and SB was directly associated with total CVD; high-light PA was not related to CVD.

Menopausal hormone therapy and the risk of cataract in postmenopausal women in South Korea

AbstractPurpose: Postmenopausal women have a higher prevalence of cataract than similar‐aged men. This study aimed to evaluate the effects of menopausal hormone therapy on lens opacity in postmenopausal women.Methods: This retrospective cohort study analysed population‐based health insurance data in South Korea collected from 2002 to 2019. To determine the risk factors associated with cataract, postmenopausal women (N = 2 506 271) were grouped according to postmenopausal hormone therapy use. The treatment group was further divided into the following subgroups: tibolone, combined oestrogen plus progestin by manufacturer, oral oestrogen, combined oestrogen plus progestin by physician, and topical oestrogen groups. The main outcome measure was the prevalence of cataract.Results: The control group comprised 463 151 postmenopausal women who had never used menopausal hormone therapy after menopause, while the treatment group included 228 033 postmenopausal women who had used menopausal hormone therapy continuously for at least 6 months. The treatment group had a higher incidence of cataract than the control group based on Cox proportional hazards ratio analysis. Low socioeconomic status and high parity were identified as risk factors for cataract, and reduced risk of cataract was associated with living in rural areas and drinking.Conclusions: Women undergoing postmenopausal hormone therapy, including tibolone, had a higher incidence of cataract than those who were not. Old age, low socioeconomic status, and high parity were risk factors for cataract. Our findings may help physicians identify postmenopausal women at a greater risk of developing cataract.

Serum Follicle-Stimulating Hormone and 5-Year Change in Adiposity in Healthy Postmenopausal Women.

Evidence from animal studies suggests that the gradual rise in follicle-stimulating hormone (FSH) during reproductive senescence may contribute to the change in adiposity distribution characteristic of menopause. The potential independent role the interrelationships of FSH and estradiol (E2) may play in postmenopausal adiposity changes are not well studied. Our objective was to evaluate the associations of FSH and dual x-ray absorptiometry (DXA)-derived adiposity measures, with consideration of estradiol and postmenopausal hormone therapy use. In a sample of 667 postmenopausal women from the Women's Health Initiative Buffalo OsteoPerio Ancillary Study, we studied the associations of serum FSH and E2 levels with dual x-ray absorptiometry (DXA)-derived adiposity measures via cross-sectional and longitudinal analyses (5-year follow-up). In cross-sectional analyses, FSH levels were inversely associated with all measures of adiposity in models adjusted for age, years since menopause, smoking status, pack-years, and hormone therapy (HT) use; these associations were not influenced by adjustment for serum E2. In longitudinal analyses, the subset of women who discontinued HT over follow-up (n = 242) experienced the largest increase in FSH (+33.9 mIU/mL) and decrease in E2 (-44.3 pg/mL) and gains in all adiposity measures in unadjusted analyses. In adjusted analyses, an increase in FSH was associated with a gain in percentage of total body fat, total body fat mass, and subcutaneous adipose tissue (SAT). While cross-sectional findings suggest that FSH is inversely associated with adiposity, our longitudinal findings suggest that greater increases in FSH were associated with greater increases in percentage of total body fat, total body fat mass, and SAT. Future studies are needed to provide additional insight into FSH-adiposity mechanisms in larger samples.

Association of Reproductive Life Span and Age at Menopause With the Risk of Aneurysmal Subarachnoid Hemorrhage.

Subarachnoid hemorrhage from cerebral aneurysm remains a devastating disease with high mortality and morbidity. Cerebral aneurysm and its rupture are more prevalent in postmenopausal women and have been postulated to be hormonally influenced. The goal of this study was to investigate the associations of female-specific factors, including reproductive life span, age at menarche, and age at menopause, with the incidence of aneurysmal subarachnoid hemorrhage (aSAH) in women. Participants in the Nurses' Health Study were followed up from 1980 or the time of reaching menopause until 2018. Only women with natural menopause or surgical menopause due to bilateral oophorectomy were included. Reproductive life span was defined by subtracting the age at menarche from the age at menopause. Multivariable-stratified proportional hazards models were used to study reproductive life span, age at menarche, and age at menopause with the incidence of aSAH. Multivariable models were adjusted for age, race, smoking, hysterectomy, hypertension, hyperlipidemia, body mass index, hormone therapy use, oral contraceptive use, and parity. A total of 97,398 postmenopausal women with reproductive life span data were included; 138 participants developed aSAH, which was confirmed on medical record review by a physician. A shorter reproductive life span (≤35 years) was associated with a 2-fold higher incidence of aSAH after multivariable adjustment (hazard ratio [HR] 2.0 [95% CI 1.4-2.8]). Early age at menopause (age <45 years) was similarly associated with a higher risk of aSAH (HR 2.1 [95% CI 1.4-3.1]), but age at menarche was not. Use of oral contraceptives and postmenopausal hormone therapy was not associated with the incidence of aSAH. An earlier age at menopause and a shorter reproductive life span duration (≤35 years) were associated with a higher risk of incident aSAH in women. No associations were noted for age at menarche, parity, oral contraceptive use, or postmenopausal therapy use.

Dietary and Supplemental Vitamin C Intake and Risk of Breast Cancer: Results from the Nurses’ Health Studies

BackgroundSome previous studies suggested that high supplemental vitamin C intake may be associated with an increased risk of breast cancer, although evidence is inconsistent. ObjectivesOur objective was to study the association between vitamin C intake and breast cancer risks using regularly updated assessments of intake over a long follow-up. MethodsWe prospectively followed 88,041 women aged 33 to 60 years from the Nurses’ Health Study (1980–2014) and 93,372 women aged 26 to 45 years from the Nurses’ Health Study II (1991–2013). A total of 11,258 incident invasive breast cancers among 181,413 women were diagnosed. Data on vitamin C intake were collected every 2–4 years via a validated FFQ and specific questions on dietary supplement use. Multivariate HRs and 95% CIs for incident invasive breast cancer were estimated with Cox models. ResultsDuring follow-up, 82% of participants ever used supplements containing vitamin C, including multivitamins. Cumulative total vitamin C intake (HR for quintiles 5 compared with 1 = 0.97; 95% CI: 0.91–1.03; Ptrend = 0.81), dietary vitamin C intake (HR for quintiles 5 compared with 1 = 0.98; 95% CI: 0.92–1.04; Ptrend = 0.57), and supplemental vitamin C intake (HR for quintiles 5 compared with 1 in users = 1.02; 95% CI: 0.94–1.09; Ptrend = 0.77) were not associated with breast cancer risks. Results were unchanged when different exposure latencies were considered. The results did not differ by menopausal status, postmenopausal hormone therapy use, or BMI. No differences were observed by estrogen receptor status of the tumor. ConclusionsOur results do not support any important association between total, dietary, or supplemental vitamin C intake and breast cancer risks.

Associations Between Endogenous Estrogen, Postmenopausal Hormone Therapy, and Cognitive Changes in Older Women

How markers of brain health are associated with endogenous estrogen and use of postmenopausal hormone therapy (HT) varies depending on women’s years from menopause and metabolic health status, ranging from potential benefit to harm. The Women’s Health Initiative (WHI) included 7,233 women age 65-80 who underwent a randomized clinical trial of various HT preparations for an average of 5.9 years. Over up to 18 years of post-trial follow-up, diabetes (DM2) increased the risk of dementia (hazard ratio [HR] 1.54 [95% CI 1.16–2.06]). Having DM2 and also treatment with unopposed conjugated equine estrogens increased the risk to HR=2.12 [1.47-3.06]. We hypothesize that the metabolic effects of estrogen in the brain drives this interaction. In support of this, the metabolic transition following menopause may alter the impact of other treatments on cognition, for example behavioral weight loss therapy to treat obesity in women with type 2 diabetes (interaction p=0.02 for executive function).

Parity, menopausal hormone therapy, and risk of ovarian granulosa cell tumor – A population-based case-control study

ObjectiveAdult-type ovarian granulosa cell tumors (AGCTs) are hormonally active neoplasms with limited epidemiological data available. We evaluated the effect of parity and postmenopausal hormone therapy (HT) use on the risk of AGCT in a population-based case-control setting. MethodsWe identified all women diagnosed with AGCT during 1994–2015 (n = 505) from the Finnish Cancer Registry. For each case, five controls matched for age were selected from the National Population Registry, which also provided data on parity and ages at deliveries. Information on postmenopausal HT by different regimens (estradiol-only, sequential estrogen-progestin and continuous estrogen-progestin) was obtained from nationwide Prescription Register. The association between parity, ages at deliveries, HT use, and AGCT incidence was evaluated by odds ratios (ORs) using a conditional logistic regression model and stratified by age at index date (<55 years or ≥ 55 years). ResultsParity and age at first or last delivery had no significant effect on AGCT risk. Systemic postmenopausal HT had been used by 20.4% of women who were later diagnosed with AGCT. The risk for subsequent AGCT was significantly decreased among users of estradiol-only therapy for at least five years (OR 0.28; 95% confidence interval 0.08–0.94) and continuous estradiol-progestin therapy for 6 months to 5 years (0.23; 0.08–0.71). ConclusionsUnlike in epithelial ovarian cancer, AGCT development is not clearly associated with parity, and users of postmenopausal HT do not seem to carry an excess risk for AGCT formation.

Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis.

BackgroundObservational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results.MethodsWe investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone–binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided.ResultsIn the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment = 1.17 [95% confidence interval = 1.00 to 1.38]; odds ratioquartile4-quartile1 = 1.33 [95% confidence interval = 0.89 to 1.97], Ptrend = .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk.ConclusionOur observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.

Prolactin and Risk of Epithelial Ovarian Cancer.

Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer. We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype. Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (P trend = 0.045; OR, quartile 4 vs. 1 = 1.34; 95% CI = 0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR = 1.38; 95% CI = 0.74-2.58; P trend = 0.32 and OR = 1.41; 95% CI = 0.93-2.13; P trend = 0.08, respectively; P heterogeneity = 0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI ≥ 25 kg/m2, but not BMI < 25 kg/m2 (corresponding OR = 2.68; 95% CI = 1.56-4.59; P trend < 0.01 and OR = 0.90; 95% CI = 0.58-1.40; P trend = 0.98, respectively; P heterogeneity < 0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis. We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI ≥ 25 kg/m2. This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

Reproductive Factors and Risk of Thyroid Cancer in Women: An Analysis in the Nurses' Health Study II.

The incidence of thyroid cancer in women is increasing at an alarming rate, with greatest risk in the reproductive years. Establishing relationships of hormonally related reproductive factors with thyroid cancer has been difficult. We aimed to elucidate potential risk factors for thyroid cancer in a large cohort of women. Among 116,228 women in the Nurses' Health Study II followed from 1989 to 2013, 620 cases of thyroid cancer were identified. We examined reproductive and hormone-related factors, including age at menarche, age at menopause, parity, oral contraceptive use, and postmenopausal hormone therapy use. Pregnancy, reproductive years, and months of breastfeeding were used as surrogate markers for exposure to endogenous reproductive hormones. We used multivariable Cox models to calculate relative risks and 95% confidence intervals for the associations between these factors and risk of thyroid cancer. Number of reproductive years of 41years or more was associated with more than double the risk of thyroid cancer compared with 30years or fewer (relative risk, 2.20; 95% confidence interval, 1.19-4.06). The other variables analyzed (parity number, months of breastfeeding, age at menarche, menopausal status, and postmenopausal hormone therapy) were not associated with the risk of thyroid cancer. Women who entered menopause at age 45years or older had a higher risk of thyroid cancer compared with women who entered menopause at a younger age. This result did not reach statistical significance; however, there was a linear trend between later age at menopause and increased risk of thyroid cancer (ptrend=.009). This study used a unique large, longitudinal dataset to assess thyroid cancer risk factors and potential confounders over an extended time frame. Our key finding suggests increased risk of thyroid cancer may be associated with a variety of indicators of longer reproductive years. The Nurses' Health Study II has provided new insights into the hormonal risks associated with thyroid cancer.

Abstract PS7-28: Association between epigenetic age acceleration and postmenopausal breast cancer risk in the Women’s Health Initiative

Abstract Earlier age of menopause and bilateral oophorectomy are associated with accelerated biologic aging based on epigenetic clocks. While these relationships suggest women with greater epigenetic age acceleration (AgeAccel) might be at a reduced risk of postmenopausal breast cancer, prior studies conflict with this theory. We hypothesized this paradox may be attributable to an interaction between epigenetic and reproductive aging on cancer risk. We evaluated this premise among 5,044 postmenopausal women in the Women’s Health Initiative (WHI) Observational Study and Clinical Trial with AgeAccel estimated in whole blood. Among a subset of 1,135 of these women, estradiol (E2) and sex hormone-binding globulin were assayed in baseline serum samples. For WHI participants with DNA methylation assays, we modeled the log odds of incident postmenopausal breast cancer during follow-up as a function of AgeAccel, adjusting for age at menopause, race/ethnicity, age at WHI screening, bilateral oophorectomy, nulliparity, alcohol consumption, smoking, body mass index, duration of postmenopausal hormone therapy use, exercise, clinical trial arm, and hysterectomy status at baseline. We repeated this analysis among the subset of participants with DNA methylation and E2 assays, and appraised the degree to which bioavailable E2 levels contributed to the observed association between AgeAccel and incident postmenopausal breast cancer. Finally, we evaluated whether bioavailable E2 levels modified the relationship between AgeAccel and cancer risk. Generalized estimating equations were used to model associations with AgeAccel, integrating repeated measures among a subset of participants and using inverse probability weights to account for sample selection probabilities. Based on our fully adjusted models, increased extrinsic AgeAccel was associated with decreased odds of incident postmenopausal invasive breast cancer during follow-up. This association was consistent among the subset of participants with E2 assays, and robust to adjustment for bioavailable E2 concentration. We found the inverse relationship between extrinsic AgeAccel and incident breast cancer was strongest among white non-Hispanic women with low levels of bioavailable E2. This study represents the largest investigation of the association between AgeAccel and postmenopausal breast cancer risk, and the first evaluation of how bioavailable E2 levels may influence this relationship. Our analyses inform our understanding of the relationship between the epigenetic and reproductive aging process, and the potential implications for postmenopausal breast cancer risk. Citation Format: Alexandra M. Binder, Lesley Tinker, Robert Wallace, JoAnn E. Manson, Lihong Qi, Parveen Bhatti, Eric A. Whitsel, Andrea Z. LaCroix, Steve Horvath. Association between epigenetic age acceleration and postmenopausal breast cancer risk in the Women’s Health Initiative [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-28.

Abstract 1143: Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas

Abstract Purpose: Oxysterols are cholesterol metabolites thought to play a role in basic carcinogenic mechanisms. One of the most abundant oxysterols in circulation is 27-hydroxycholesterol (27HC), which has been shown to be an endogenous selective estrogen receptor modulator and implicated in breast cancer etiology. 27HC is a ligand for liver X receptors expressed in the liver, gut, adipose tissue, and macrophages. In the colorectum, expression of these receptors suppresses cellular proliferation. It is unknown whether circulating 27HC is associated with the risk of developing colorectal neoplasia. Methods: Circulating 27HC was measured in plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed placebo-controlled randomized clinical trial of daily supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. Participants were 2,259 men and women, 45-75 years old, diagnosed with ≥1 colorectal adenoma within 120 days prior to enrollment. Each was followed for new colorectal adenomas during a 3- or 5-year colonoscopy surveillance interval. 27HC concentrations were quantified using high-performance liquid chromatography/mass spectrometry for those who reported fasting ≥8 hours at the time of blood draw. Premenopausal women and postmenopausal women currently using hormone therapy were excluded from analyses. Risk ratios (RR) and 95% confidence intervals (CI) were estimated from log-linear regression models with adjustment for sex, age, race/ethnicity, body mass index, smoking status, family history of colorectal cancer, aspirin use, nonsteroidal anti-inflammatory drug use, and former use of postmenopausal hormone therapy. High-risk colorectal adenoma findings were defined as ≥1 advanced adenoma (≥1 cm in diameter, with 25% villous components, high-grade dysplasia, or adenocarcinoma) or ≥3 synchronous adenomas of any type. Secondary analyses considered results stratified by sex and anatomic location of lesions (proximal colon vs. distal colon/rectum). Results: In total, 27HC was measured for 1,246 participants (894 men and 352 women). Circulating 27HC was higher among men (mean, 181 ng/mL; standard deviation, SD, 49 ng/mL) than among postmenopausal women (mean, 154 ng/mL; SD, 46 ng/mL). During follow-up, 596 (46%) participants were diagnosed with ≥1 new colorectal adenoma. Circulating 27HC was associated with 9% higher risk of any colorectal adenoma per SD increase (RR, 1.09; 95% CI, 1.02-1.15; P=0.008) and 19% higher risk of high-risk colorectal adenoma findings per SD increase (RR, 1.19; 95% CI, 1.07-1.33; P=0.002). Sex-stratified results were of similar magnitude, and there were no meaningful differences according to anatomic location of adenomas. Conclusions: Circulating 27HC concentration may be a novel risk factor for metachronous colorectal adenomas. Citation Format: Michael N. Passarelli, Bonne M. Thompson, Jeffrey G. McDonald, Thomas J. Palys, Judy R. Rees, Elizabeth L. Barry, John A. Baron. Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1143.

Postmenopausal hormone therapy in BRCA gene mutation carriers: to whom and which?

ABSTRACT Introduction Risk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause. Areas covered To evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC. Expert opinion All BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to ‘progestin-free’ HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these ‘progestin-free’ preparations and BC safety.

Postmenopausal Hormone Therapy Is Primarily Associated with Reduced Risk of Colorectal Cancer Arising through the Adenoma-Carcinoma Pathway

Abstract Our goal was to evaluate whether the inverse association of postmenopausal hormone therapy (PMH) and colorectal cancer (CRC) differs by molecularly defined CRC tumor subtypes. Methods: We pooled data on tumor markers and PMH use among 8,220 post-menopausal women (3,898 CRC cases and 4,322 controls) from eight observational studies in the Genetics of Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of ever versus never PMH use and each tumor subtype compared with controls. We defined subtypes according to microsatellite instability (MSI-high or -low/stable), CpG island methylator phenotype (CIMP positive or negative), oncogenic mutations in BRAF and KRAS, and combinations of these markers that have been linked to specific pathways (adenoma-carcinoma, serrated, alternate). Additionally, we investigated whether associations varied by tumor anatomic location (proximal colon, distal colon, rectum). All models were adjusted for study, age, body mass index, smoking status, and family history of CRC. Wald chi-square tests were used to evaluate whether the association differed by tumor-specific subtypes. Results: Ever use of PMH was associated with a 38% reduction in overall CRC risk (OR 0.62, 95% CI 0.56–0.69). In general, this association was observed regardless of individual markers for MSI, CIMP, BRAF, or KRAS status. However, when taken altogether and grouping cases by pathway, the association was attenuated for tumors arising through the serrated pathway compared with the adenoma-carcinoma pathway (OR 0.81, 95% CI 0.65–1.01; p for difference 0.046). We also observed a weaker association for tumors of the proximal colon compared with the distal colon and rectum (OR 0.71, 95% CI 0.62–0.80; p for difference 0.010). Conclusions: In this large consortium analysis, we observed a strong inverse association between PMH use and overall CRC risk. The association may predominantly reflect a benefit of PMH use for tumors arising through the adenoma-carcinoma pathway and tumors of the distal colon and rectum, as the association was weaker for tumors arising through the serrated pathway and proximal colon tumors.

Interaction between postmenopausal hormone therapy and diabetes on cataract.

We investigated whether postmenopausal hormone therapy (HT) use interacts with diabetes, a risk factor for several age-related eye diseases. A cross-sectional analysis of women involved in the Canadian Longitudinal Study on Aging was performed. The random sample comprised of 15,320 community-dwelling women between ages 45 and 85 years old sampled from areas adjacent to 11 data collection centers across Canada. Information on menopausal status and HT were collected by self-report. Data on diabetes and eye disease were obtained by self-report of a physician diagnosis. Multivariable logistic regression was used. After adjusting for demographic, lifestyle, and health variables, a multiplicative interaction was identified such that HT use for 10 years or more was associated with a much higher odds of a report of cataract in women with type 2 diabetes (odds ratio = 2.44, 95% confidence interval 1.49, 3.99) but not in long-term HT users with no diabetes (odds ratio = 1.03, 95% confidence interval 0.87, 1.21) (interaction term P value = 0.013). HT use was not associated with glaucoma or macular degeneration. Long-term HT use and type 2 diabetes interact in their relationship with cataract. This novel finding should be confirmed. If confirmed, women with type 2 diabetes should be informed that long-term HT use increases their risk of cataract. : Video Summary:http://links.lww.com/MENO/A519.

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort.

Endometrial cancer (EC) incidence rates vary ~10‐fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low‐risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow‐up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non‐HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.

Impact of Sex Hormones, Postmenopausal Hormone Therapy and Risk Factors on Development of Abdominal Aortic Aneurysm in Women: A Population-based Prospective Study in Norway: A Hunt Study

Introduction - Women develop abdominal aortic aneurysms (AAA) five to ten years later than men (1,2). The delay in AAA development may be secondary to a protection from estrogens (3,4). The aim of the present study was to evaluate the impact of risk factors associated with AAA development in women, including postmenopausal hormone therapy. This has previously been investigated in small cohorts with limited information. Methods - In a total cohort of 106,000 individuals from the Norwegian Nord-Trøndelag Health Study (HUNT), 20,024 postmenopausal women were identified, of which 201 developed AAAs during a median follow-up of 18 years (1995-2014, i.e. 295,554 person-years). The data is based on questionnaires, physical measurements, medical records and blood samples. A multivariable Cox regression model was constructed, where the final adjusted model included the following variables: smoking (current, past, never), body mass index, coronary heart disease, diabetes, hypertension and postmenopausal hormone therapy. Multiple imputation was performed for missing data (n=50 data sets). Serum estradiol concentrations were compared between women who later did or did not develop AAAs. Median time from blood sample collection to AAA diagnosis was seven years. Results - Mean age at AAA diagnosis was 77 (59 -100) years. 28% of the cohort reported ever use of postmenopausal hormone therapy. In the multivariable analysis, a notable Hazard ratio (HR) of 0.58 was observed for current use of hormone therapy, but the result was not statistically significant (95% CI 0.29-1.16, p=0.12). Women who reported current smoking had a more than ten-fold risk for developing AAA during follow-up (HR 10.9 (7.4-16.1)). Positive associations were also found for hypertension (HR 2.0 (1.4-3.0)) and coronary heart disease (HR 2.2 (1.6-3.2)). There was no substantial difference in estradiol concentrations between women with and without AAA (p=0.06). Conclusion - Postmenopausal hormone therapy is of less clinical importance compared to the strong associations observed between smoking, hypertension coronary heart disease and AAA development in women. These findings were supported by measured estradiol concentrations.