Hormone Replacement Therapy Nonusers Research Articles

Exogenous hormone use and the risk of surgically treated cataract: Evidence from 91 760 female participants in the 45 and Up Study.

To investigate the association between exogenous hormone use and the risk of cataract surgery among working-aged Australian women. A total of 91 760 female participants aged 45-65 years and without prior history of cataract surgery were prospectively enrolled between January 2006 and December 2009 in New South Wales (NSW), Australia. A baseline self-reported questionnaire was used to collect information on participant demographic, socio-economic, lifestyle characteristics, medical history as well as the use of hormonal contraception and hormone replacement therapy (HRT). Cataract surgery for these participants during 2006-2019 was determined according to the Medicare Benefits Schedule database. Cox regression was used to assess the association between exogenous hormone use and incident cataract surgery during the follow-up. During a mean follow-up of 11.3 years, 10 444 participants underwent cataract surgery with a corresponding incidence of 11.4% (10 444/91 760). Compared with never users, ever and current users of HRT had a 22% and 14% increased risk of cataract surgery, respectively. A dose-response with longer HRT use resulting in a larger increase in cataract surgery risk was observed (p for trend <0.001). Among participants never used HRT, hormonal contraception had a protective effect against incident cataract surgery (hazards ratio: 0.87; 95% confidence interval: 0.80-0.94). Use of HRT significantly increased the risk of cataract surgery, and hormonal contraception use had a protective effect on cataract surgery among HRT non-users. Further studies assessing the effect of different hormone types and doses are needed.

Comparison of Fundamental Frequency in Postmenopausal Women Who Are Treated With Hormone Replacement Therapy vs Those Who Are Not

Hormonal changes during menopause have been associated with significant changes in voice. Although hormone replacement therapy (HRT) is used primarily to manage systemic symptoms of menopause, its association with voice in postmenopausal women has not been adequately investigated by large-scale studies. To compare fundamental frequency between postmenopausal women who used HRT and those who did not use HRT. PubMed, Ovid MEDLINE, CINAHL, Cochrane EBM Reviews, and Embase were searched from 1946 to February 19, 2020. Studies included in the final review were those in English that compared voice outcomes in postmenopausal women who were or were not receiving HRT for treatment of climacteric symptoms associated with menopause. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction was performed by 2 independent investigators. Study quality was assessed using a validated quality tool. Whenever possible, data were pooled using random-effects meta-analysis. The primary outcome was the difference in speaking fundamental frequency (F0) between HRT users and nonusers. Subgroup analysis of the primary outcome was based on body mass index (BMI) using a cutoff value of 25. A BMI of 18.5 to 24.9 is considered normal, and a BMI of at least 25 is considered overweight. Secondary outcomes included other objective measurements of voice, including jitter and shimmer. A total of 937 records were screened, 18 full texts were assessed, and 11 studies were included in the final review. All 11 studies were case-control studies and were rated from fair to good quality based on the Newcastle-Ottawa Scale. A total of 5 studies including 154 participants who received HRT and 154 controls were used for meta-analysis. The mean (SD) F0 was 185.9 (8.6) Hz for HRT users compared with 174.6 (6.6) Hz for nonusers. Hormone replacement therapy was associated with a higher mean F0 by a difference of 11.85 Hz (95% CI, 7.35-16.36 Hz). Subgroup analysis showed that the change in F0 was significant in postmenopausal women with a normal body mass index (mean difference, 13.47 Hz; 95% CI, 8.48-18.46 Hz) but not in those with a high body mass index. Existing evidence suggests that HRT is associated with a higher F0 in postmenopausal women. The effectiveness of the treatment appeared to be more pronounced in women with a normal body mass index.

Hormone Replacement Therapy, Breast Cancer Risk Factors, and Breast Cancer Risk: A Nationwide Population-Based Cohort.

Hormone replacement therapy (HRT) increases the risk of breast cancer, but the association may vary according to patient factors. We investigated the association between HRT and breast cancer in a nationwide cohort with risk stratification according to risk factors for breast cancer. Using the Korean National Health Insurance Service database, 4,558,376 postmenopausal women who underwent breast cancer screening and regular health checkups from 2009 to 2014 were analyzed. A total of 696,084 (15.3%) women reported current or previous HRT use. Breast cancer was newly diagnosed in 26,797 (0.6%) women during a median follow-up of 5.35 years. The HR of the risk of breast cancer in HRT users was 1.25 [95% confidence interval (CI), 1.22-1.29] compared with HRT nonusers. The risk of breast cancer increased according to HRT duration [adjusted HR = 1.08; 95% CI, 1.04-1.12, for <2 years; adjusted HR = 1.33; 95% CI, 1.25-1.40, for 2 to <5 years; and adjusted HR = 1.72; 95% CI, 1.63-1.82, for ≥5 years). The effects of HRT on breast cancer risk applied to both invasive and in situ cancer. The HRT-related risk of breast cancer was higher in women who were leaner and those who had dense breasts. This nationwide population-based study confirms the association between HRT use and breast cancer risk. The risk increased proportionally with duration of HRT and differed according to body weight and breast density. Risk stratification would be useful when deciding whether to apply HRT for relief of menopausal symptoms.

MP43-11 PROTECTIVE EFFECT OF POSTMENOPAUSAL HORMONE REPLACEMENT AGAINST UROLITHIASIS

INTRODUCTION AND OBJECTIVE: Menopause is reported to be associated with increased urinary calcium excretion, which may enhance the risk for the development of urolithiasis. However, it remains controversial about whether postmenopausal hormone replacement is a risk factor for formation of urolithiasis. Therefore, we conducted a population-based retrospective cohort study to evaluate the effect of hormone replacement therapy (HRT) on the formation of urolithiasis. METHODS: We used data sourced from Longitudinal Health Insurance Database, which consists of one million randomly selected subjects from the National Health Insurance Research Database of Taiwan. Health Insurance System of Taiwan covers approximately 23 million people (98% of population). Women who were prescribed HRT continually for longer than 3 months during 1997 to 2009 were classified as HRT users; the others were classified as non-users. A total of 13724 HRT users aged ≥ 45 years in 1997 without previous diagnosis of urolithiasis were enrolled. A cohort of 13724 age and metabolic syndrome matched non-HRT users were enrolled as the control group. HRT users were followed from the date of commencing HRT until six months after discontinuation of HRT. Non-users were followed from 1 January 1997 to 31 December 2009. Stratified cox regression model was used to examine the risk of subsequent urolithiasis between HRT users and non-users. RESULTS: Of the sampled patients, HRT users had a significantly lower cumulative incidence of urolithiasis than non-users (4.66% vs 5.94%, p < 0.001). The log-rank test revealed that HRT users had significantly higher urolithiasis-free survival rates than non-users (p < 0.001). HRT users were found to be at 0.78 times the risk of urolithiasis than non-users (95% confidence interval 0.70–0.87, p < 0.001). We further divided the HRT users into two groups according to HRT regimens: estrogen-only vs estrogen combined with progestin. The hazard ratio for urolithiasis in the estrogen-only HRT users compared with non-users was 0.78 (95% confidence interval 0.61–0.99, p = 0.04) and 0.78 (95% confidence interval 0.70–0.88, p < 0.001) in the patients with combined regimen. CONCLUSIONS: HRT use was associated with a lower risk of urolithiasis independent of the regimen difference. Source of Funding: None

Psychological behavior patterns and coping with menopausal symptoms among users and non-users of hormone replacement therapy in Finnish cohorts of women aged 52–56 years

ObjectiveTo identify subgroups of women who differ with respect to self-evaluated stress, hostility, optimism and sense of coherence, and to identify differences, if any, in whether these subgroups use or do not use hormone replacement therapy (HT). Study design and methodsThis time-trend study is based on the Finnish national HeSSup study, in which nationwide cohorts of Finnish women aged 52–56 years randomly selected in 2000 (n = 1321) and in 2010 (n = 1389) responded to postal questionnaires related to four psychological behavior patterns. Main outcome measuresRelationships between psychological behavior patterns (stress, hostility, optimism and sense of coherence) and how menopausal symptoms are experienced and how this relates to the use of HT. ResultsThe proportion of HT users was higher among those with more stress and hostility and less optimism and sense of coherence than among those low in stress and hostility and high in optimism and sense of coherence. ConclusionsDifferences in psychological behavior patterns influence the perception of menopausal symptoms and the use of HT. When the treatment of women at menopause is planned, psychological behavior patterns should be considered, as these reflect the ability to cope with menopausal symptoms.

Hormone replacement therapy decreases the risk of tinnitus in menopausal women: a nationwide study.

The incidence and risk of tinnitus associated with hormone replacement therapy (HRT) in menopausal women have not yet been fully examined. We examined the medical records of menopausal women aged between 45 and 79 years from Taiwan's National Health Insurance Research Database of records between 1 January 2000 and 31 December 2010 to establish matched cohorts (13,920 HRT users and 41,760 nonusers). The incidence of tinnitus in HRT users and nonusers were matched 1:3 based on propensity-score matching over this ten year period. The Cox regression hazard model was used to identify risk factors of tinnitus, and results indicate that a significantly lower percentage of HRT users (P = 0.017) developed tinnitus in comparison with nonusers (0.43%, 60/13, 920 vs. 0.59%, 246/41, 760). Using Cox regressions analysis after adjustments for age and other variables (adjusted hazard ratio: 0.505 (95% confidence interval, 0.342–0.756)), we were also able to show that HRT users appeared to have a reduced risk of developing tinnitus in comparison with nonusers. Based on our observation of the lower incidence of tinnitus among HRT users in this cohort, we speculate that HRT may have provided potential benefits on the management and prevention of tinnitus among menopausal women.

Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies.

We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05–1.22), and for per year increases was 1.02 (95% CI = 1.02–1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56–1.96), and for per year increases was 1.08 (95% CI = 1.08–1.08). Dose-response analyses revealed 8–10 years’ onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER-positive than negative BC cases were detected among EPT users.

Association of Catechol-O-methyltransferase polymorphism Val158Met and mammographic density: A meta-analysis

ObjectivesThe Val158Met polymorphism in catechol-O-methyltransferase (COMT) enzyme reduces the methylation of catechol estrogens, which may affect mammographic density. High mammographic density is a known risk factor of breast cancer. Our aim was to perform meta-analysis of the effect of COMT Val158Met polymorphism on mammographic density. MethodsOriginal studies reporting data on mammographic density, stratified by the presence of COMT Val158Met polymorphism, were identified and combined using genetic models Met/Val vs. Val/Val, Met/Met vs. Val/Val, Val/Met+Met/Met vs. Val/Val (dominant model) and Met/Met vs. Val/Met+Val/Val (recessive model). Subgroup analyses by breast cancer status, menopausal status and use of hormone replacement therapy (HRT) were also performed. ResultsEight studies were included in the meta-analysis. The overall effect in percent mammographic density was −1.41 (CI −2.86 to 0.05; P=0.06) in the recessive model. Exclusion of breast cancer patients increased the effect size to −1.93 (CI −3.49 to −0.37; P=0.02). The results suggested opposite effect of COMT Val158Met for postmenopausal users of HRT versus premenopausal women or postmenopausal non-users of HRT. ConclusionsCOMT Val158Met polymorphism may be associated with mammographic density at least in healthy women. Menopausal status and HRT should be taken into account in future studies to avoid masking of the underlying effects.

Leukocyte and Skeletal Muscle Telomere Length and Body Composition in Monozygotic Twin Pairs Discordant for Long-term Hormone Replacement Therapy.

Estrogen-based hormone replacement therapy (HRT) may be associated with deceleration of cellular aging. We investigated whether long-term HRT has effects on leukocyte (LTL) or mean and minimum skeletal muscle telomere length (SMTL) in a design that controls for genotype and childhood environment. Associations between telomeres, body composition, and physical performance were also examined. Eleven monozygotic twin pairs (age 57.6 ± 1.8 years) discordant for HRT were studied. Mean duration of HRT use was 7.3 ± 3.7 years in the user sister, while their co-twins had never used HRT. LTL was measured by qPCR and SMTLs by southern blot. Body and muscle composition were estimated by bioimpedance and computed tomography, respectively. Physical performance was measured by jumping height and grip strength. HRT users and non-users did not differ in LTL or mean or minimum SMTL. Within-pair correlations were high in LTL (r = 0.69, p = .020) and in mean (r = 0.74, p = .014) and minimum SMTL (r = 0.88, p = .001). Body composition and performance were better in users than non-users. In analyses of individuals, LTL was associated with BMI (r 2 = 0.30, p = .030), percentage total body (r 2 = 0.43, p = .014), and thigh (r 2 = 0.55, p = .004) fat, while minimum SMTL was associated with fat-free mass (r 2 = 0.27, p = .020) and thigh muscle area (r 2 = 0.42, p = .016). We found no associations between HRT use and telomere length. Longer LTLs were associated with lower total and regional fat, while longer minimum SMTLs were associated with higher fat-free mass and greater thigh muscle area. This suggests that telomeres measured from different tissues may have different associations with measures of body composition.

Hormonal Status As Determinant Of Serum Exosomal MicroRNA Content In Pre- And Postmenopausal Women

PURPOSE:This study investigates the effect of systemic sex steroid status on microRNA content of circulating exosomes (exomiRs) among adult women who differ in menopausal status and use of hormone replacement therapy. Exosomes are small vesicles secreted from various cell types. They function in the intercellular communication as carriers for genetic material, such as mRNAs and microRNAs. We have previously shown that there are specific freely circulating microRNAs which are sensitive for systemic sex steroid status. Therefore, we hypothesized that also the systemic exomiR content might vary according to the circulating estrogen levels. METHODS:We analysed the exomiR content from serum samples of premenopausal women (n=8, 30-40 yrs) and from genetically identical postmenopausal female twin pairs (n=10 pairs, 54-62 yrs) discordant for the use of estrogen based hormone replacement therapy (HRT). Serum exosomes were extracted with precipitation solution followed by RNA extraction by Trisure reagent. Library preparation was performed by TruSeq Small RNA sample preparation protocol (Illumina) and microRNAs were sequenced by MiSeq Desktop Sequencer (Illumina). Data analysis was performed using a customized work-flow including miRDeep2 for microRNA identification and the edgeR R-package for identification of differentially expressed (DE) exomiRs. RESULTS:In total, 241 different exomiRs were detected on the basis of sequencing. The most commonly expressed exomiRs included mir-486-5p, -92a-3p, -16-5p, -451a and -22-3p. In the DE analysis 11 miRs were up- and 20 miRs downregulated significantly in HRT non-users when comparing them to premenopausal women (nominal p<.05). DE between the postmenopausal HRT users and premenopausal women showed that 6 miRs were up- and 10 downregulated in HRT users (nominal p<.05). DE between the HRT non-user and user co-twins showed that 5 miRs were up- and 6 downregulated in non-users (nominal p<.05). CONCLUSIONS:Aging- and HRT association with sequenced exomiRs was detected, which warrants further studies, including validation by RT-qPCR, to understand the functional role of exomiRs as potential mediators of hormonal aging process. Funding:The Academy of Finland, Finnish Culture Foundation, The Ministry of Education and Culture and EFCP7 Collaborative project MYOAGE

Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival.

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs.

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes’ IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort.

Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors. Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects. Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor. Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.

A Meta-Analysis of Reference Values of Leptin Concentration in Healthy Postmenopausal Women

ObjectiveThere are numerous reports about the leptin concentration (LC) in postmenopausal women (PW). Changes in LC can elicit different clinical outcomes. We systematically analyzed the LC in PW.MethodsA search was conducted in original English-language studies published from 1994 to October 2012 in the following databases: Medline (78), Cochrane Center (123) Embase (505), Biological abstracts (108), Cochrane (53) and Science Finder Scholar (0). A meta-analysis was undertaken on the correction coefficient (r) between the serum LC and body mass index (BMI) for healthy PW across studies containing a dataset and sample size. Pre-analytical and analytical variations were examined. Pre-analytical variables included fasting status (FS) and sampling timing. Analytical variation comprised assay methodology, LC in those undertaking hormone replacement therapy (HRT) and those not having HRT as well as LC change according to age.ResultsTwenty-seven studies met the inclusion criteria. Eighteen studies detected LC in the morning in a FS, 15 studies denoted the r between leptin and the BMI. A combined r was counted for the 15 studies (r = 0.51 [95% confidence interval (CI), 0.46–0.54], P = 0.025), and if sampling collection was in the FSat morning, a combined r was form 10 studies (r = 0.54 [95% CI, 0.45–0.54], P = 0.299) and heterogeneity was diminished. LC did not change between HRT users and non-users in 7 studies. Five studies analyzed changes in LC according to age.ConclusionBased on all studies that investigated both LC and BMI, LC was positively correlated with the BMI. No studies established reference ranges according to the Clinical and Laboratory Standards Institute (CLSI) in healthy PW, and there was a wide variation in LC values. These differences suggest that caution should be used in the interpretation and comparison between studies.

Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case–control study in Italy

Background:Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells.Methods:In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case–control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors.Results:Women in the highest quartile category of proanthocyanidins with ⩾3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48–0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m−2, and, for flavanones, among parous or non-users of hormone-replacement therapy women.Conclusion:High consumption of selected proanthocyanidins may reduce endometrial cancer risk.

Distribution and determinants of C‐reactive protein in the older adult population: European Prospective Investigation into Cancer‐Norfolk study

C-reactive protein (CRP) is a well-documented predictor of cardiovascular diseases and mortality. We aimed to better understand the distribution and determinants of CRP in the population. Study participants were men and women aged 40-79 in the UK-based EPIC-Norfolk population-based cohort study. CRP was measured in 18 586 available serum samples (8334 men and 10 252 women) and remeasured in 6087 individuals on average 13 years later using a high-sensitivity assay. In cross-sectional analyses, the range of serum CRP was 0.1-188.3 mg/L and the median 1.6 mg/L. A third of the population had serum CRP levels above 3 mg/L. Serum CRP levels were comparable in men and women who were not taking postmenopausal hormone replacement therapy (HRT). Women who were taking HRT had double CRP levels compared with HRT nonusers. Smoking was also strongly related to CRP in men and women. Serum CRP was positively and independently associated with age, body mass index and waist circumference and inversely with height. A stronger association with serum CRP measured concurrently than on average 13 years later indicated a short-term rather than long-term association with smoking and HRT use. Social class and alcohol intake were not independently related to CRP, but there was a strong inverse association with educational status. The distribution of serum CRP in the population is similar in men and women after taking into account smoking and HRT use. Anthropometric factors as well as educational status are strongly related to serum CRP.

Plasma 25‐hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case–control study

Experimental evidence suggests that vitamin D might play a role in the development of breast cancer. Although the results of case-control studies indicate that circulating 25-hydroxyvitamin D [25(OH)D] is inversely associated with the risk of breast cancer, the results of prospective studies are inconsistent. A case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) was carried out comprising 1,391 incident breast cancer cases and 1,391 controls. Multivariable conditional logistic regression models did not reveal a significant overall association between season-standardized 25(OH)D levels and the risk of breast cancer (ORQ4-Q1 [95% CI]: 1.07 [0.85-1.36], ptrend = 0.67). Moreover, 25(OH)D levels were not related to the risks of estrogen receptor positive tumors (ORQ4-Q1 [95% CI]: 0.97 [0.67-1.38], ptrend = 0.90) and estrogen receptor negative tumors (ORQ4-Q1 [95% CI]: 0.97 [0.66-1.42], ptrend = 0.98). In hormone replacement therapy (HRT) users, 25(OH)D was significantly inversely associated with incident breast cancer (ORlog2 [95% CI]: 0.62 [0.42-0.90], p = 0.01), whereas no significant association was found in HRT nonusers (ORlog2 [95% CI]: 1.14 [0.80-1.62], p = 0.48). Further, a nonsignificant inverse association was found in women with body mass indices (BMI) < 25 kg/m(2) (ORlog2 [95% CI]: 0.83 [0.67-1.03], p = 0.09), as opposed to a borderline significant positive association in women with BMI ≥ 25 kg/m(2) (ORlog2 [95% CI]: 1.30 [1.0-1.69], p = 0.05). Overall, prediagnostic levels of circulating 25(OH)D were not related to the risk of breast cancer in the EPIC study. This result is in line with findings in the majority of prospective studies and does not support a role of vitamin D in the development of breast cancer.

Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer

BackgroundBreast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT).MethodsWe analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model.ResultsOne SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing.ConclusionsWe conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Longitudinal Associations of the Endocrine Environment on Fat Partitioning in Postmenopausal Women

Among postmenopausal women, declining estrogen may facilitate fat partitioning from the periphery to the intra-abdominal space. Furthermore, it has been suggested that excess androgens contribute to a central fat distribution pattern in women. The objective of this longitudinal study was to identify independent associations of the hormone milieu with fat distribution in postmenopausal women. Fifty-three healthy postmenopausal women, either using or not using hormone replacement therapy (HRT) were evaluated at baseline and 2 years. The main outcomes were intra-abdominal adipose tissue (IAAT), subcutaneous abdominal adipose tissue, and total thigh fat analyzed by computed tomography scanning and leg fat and total body fat mass measured by dual-energy X-ray absorptiometry. Serum estradiol, estrone, estrone sulfate, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate), sex hormone-binding globulin (SHBG), and cortisol were assessed. On average, in all women combined, IAAT increased by 10% (10.5 cm(2)) over 2 years (P < 0.05). Among HRT users, estradiol was inversely associated with, and estrone was positively associated with, 2-year gain in IAAT. Among HRT nonusers, free testosterone was inversely associated with, and SHBG was positively associated with, 2-year gain in IAAT. These results suggest that in postmenopausal women using HRT, greater circulating estradiol may play an integral role in limiting lipid deposition to the intra-abdominal cavity, a depot associated with metabolically detrimental attributes. However, a high proportion of weak estrogens may promote fat partitioning to the intra-abdominal cavity over time. Furthermore, among postmenopausal women not using HRT, greater circulating free testosterone may limit IAAT accrual.

Dydrogesterone does not reverse the cardiovascular benefits of percutaneous estradiol

ABSTRACTObjective To evaluate the influence of dydrogesterone on estimated cardiovascular risk of users of hormone replacement therapy (HRT) (with percutaneous 17β-estradiol in monotherapy and in combination with dydrogesterone) and HRT non-users through the Framingham score tool for a period of 2 years.Methods Framingham scores were calculated from the medical records of patients treated for at least 2 years with 17β-estradiol alone or in combination with dydrogesterone, along with HRT non-users, through the analysis of patient medical records, followed for at least 2 years at Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione.Results Improvements in lipid profile, glucose and blood pressure levels, which reduced the estimated cardiovascular risk, were observed in the 17β-estradiol group. Similar changes were observed in the users of 17β-estradiol + dydrogesterone, suggesting that this progestogen does not attenuate the effects caused by 17β-estradiol.Conclusions Both HRT groups showed a reduction in their Framingham score. In contrast to data from other HRT investigations on cardiovascular risk, these formulations proved to be safe, even in the first year of use.