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Background and ObjectivesPrevious studies on the relationship between body mass index (BMI) and Parkinson disease (PD) provided inconsistent results, likely due to reverse causation explained by weight loss during the prodromal phase. We examined the association of BMI and abdominal adiposity with PD incidence using lagged analyses to address the potential for reverse causation and compared BMI trajectories in patients before diagnosis and matched controls.MethodsWe used data from the E3N cohort study of French women with a 29-year follow-up (1990–2018). BMI (kg/m2) was computed based on self-reported weight and height up to 11 times; up to 6 waist circumference (WC) and hip circumference measures were available. PD diagnoses were validated based on medical records and drug claim databases. Multivariable time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs according to BMI categories (underweight 2; normal = [18.5–25.0[ kg/m2; overweight = [25.0–30.0[ kg/m2; obese ≥30.0 kg/m2). Exposures were lagged by 5 years in main analyses; we used longer lags (10 and 20 years) in sensitivity analyses. We examined trajectories of BMI categories within a nested case-control study using multivariable generalized estimating equations multinomial logistic models.ResultsOf 96,702 women (baseline age = 40–65 years), 1,164 developed PD. PD incidence was lower (HR = 0.76, 95% CI = 0.59–0.98,p= 0.032) among women with obesity compared with those with normal BMI. There was a similar association in analyses using longer lag times (20 years, 598 cases, HR = 0.52, 95% CI = 0.30–0.88,p= 0.016). A similar pattern was seen for WC and waist-height ratio but not waist-hip ratio. Trajectories of BMI categories (1,196 patients and 23,876 controls) showed that obesity was less frequent in patients with PD before diagnosis than in controls, with a statistically significant difference 29 years before. In addition, the frequency of obesity decreased 5–10 years before diagnosis in patients.DiscussionIn this large cohort of women with a long follow-up, obesity was associated with a lower hazard of PD, even when measured 20 years before diagnosis, in agreement with Mendelian randomization studies. Our analyses underscore the importance of lagged analyses to account for reverse causation. These findings warrant further investigations to understand the mechanisms underlying this inverse association.

International audience; Background: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose–response relations based on time-varying exposures. Objectives: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. Method: We used data from the E3N cohort study of French women (follow-up, 2004–2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins–PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. Results: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54–79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67–1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51–0.98), with a dose–response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. Conclusion: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose–response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98 068 women aged 40–65 years in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the timescale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (

International audience

International audience; Introduction: Migraine and combined hormonal contraceptives (CHCs) increase the risk of ischemic stroke in young women; however, the contribution of low-dose (

International audience; BACKGROUND AND AIM - Air pollution exposure negatively affects human health and might also be linked to frailty. We aimed to evaluate whether exposure to air pollution is associated with poorer handgrip strength, a marker of frailty. METHODS - Data from the enrollment phase of the French CONSTANCES cohort participants aged 45-years and more were analyzed cross-sectionally. Modeled concentrations of PM2.5, black carbon, and NO2 from the ELAPSE land-use regression model were assigned to the residential address of each participant. Sex-specific maximum handgrip strength (HGSmax) was used as an outcome in multilevel linear regression models adjusted for a set of confounders (reported as β and 95% confidence interval (CI)), using the center of recruitment as a clustering factor. Subgroup analyses were performed across different levels of urbanicity and different personal variables including clinical risk factors. RESULTS - Of the 53,379 participants (mean age 57.4±7.2 years), 50.3% were women. The median concentration of PM2.5, black carbon, and NO2 was 16.1 (IQR=3.8) µg/m3, 1.6 (IQR=0.7) 10-5/m, and 22.5 (IQR=13.7) µg/m3, respectively. HGSmax in men was significantly higher than in women (42.1 vs. 25.6 kg). Exposure to all the three pollutants was associated with lower HGSmax in both sexes (e.g. β= -0.08; 95% CI: -0.11: -0.04 in men, and β= -0.08; 95% CI: -0.12: -0.04 in women per 3.8 µg/m3 exposure to PM2.5 in the adjusted model). Significantly stronger associations were found for all three pollutants (in single pollutant models) in men aged 65 years and older compared to younger men. Men with diabetes, depression, and cardiovascular disease tended to have poorer HGSmax associated with exposure to all of the pollutants. Stratified results for women were less conclusive. CONCLUSIONS - In this large general population study, air pollution was associated with poorer HGS, especially in men. It is of importance because HGS is a marker of general well-being and frailty.

BACKGROUND/OBJECTIVES The associations of reproductive history and motor function are controversial. DESIGN Prospective cohort study with 10 years of follow-up. SETTING Three French cities between 1999 and 2011. PARTICIPANTS A total of 3043 community-dwelling women from the Three-City Dijon study population. MEASUREMENTS We examined the cross-sectional and longitudinal association of age at menopause, artificial menopause, and parity with walking speed (WS) using linear regression and linear mixed models, respectively. Cox proportional models were used to examine the association of characteristics of reproductive life with disability. RESULTS Mean baseline WS was 143.8 cm/s. Artificial menopause was associated with slower WS at baseline (β = -3.29; 95% confidence interval [CI] = -5.83 to -0.74; P = .01). Reproductive life characteristics had no effect on change in WS. Increasing age at menopause was associated with reduced disability risk (hazard ratio [HR] for 5-year increase = 0.92; 95% CI = 0.87-0.99; P = .02), while parity increased disability risk (HR for ≥3 vs 0 children = 1.53; 95% CI = 1.22-1.93; P

BACKGROUND Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. METHODS This population-based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to DSM-IV criteria. Seven single-nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. RESULTS Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p-values .01 to .0005). Three SNPs were associated with an increased risk of late-life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. CONCLUSIONS Variants of the CYP19A1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.

Background Previous studies have shown conflicting results regarding the influence of cardiovascular risk-factors on venous thromboembolism. This study aimed to determine if these risk-factors, i.e. physical activity, smoking, hypertension, dyslipidaemia, and diabetes, were associated with the risk of venous thromboembolism, and to determine if these associations were confounded by BMI. Methods We used data from the E3N cohort study, a French prospective population-based study initiated in 1990, consisting of 98,995 women born between 1925 and 1950. From the women in the study we included those who did not have prevalent arterial disease or venous thromboembolism at baseline; thus 91,707 women were included in the study. Venous thromboembolism cases were self-reported during follow-up, and verified via specific mailings to medical practitioners or via drug reimbursements for anti-thrombotic medications. Hypertension, diabetes and dyslipidaemia were self-reported validated against drug reimbursements or specific questionnaires. Physical activity, and smoking were based on self-reports. Cox-models, adjusted for BMI and other potential risk-factors were used to determine hazard ratios for incident venous thromboembolism. Results During 1,897,960 person-years (PY), 1, 649 first incident episodes of thrombosis were identified at an incidence rate of 0.9 per 1000 PY. This included 505 cases of pulmonary embolism and 1144 cases of deep vein thrombosis with no evidence of pulmonary embolism. Hypertension, dyslipidaemia, diabetes, smoking and physical activity were not associated with the overall risk of thrombosis after adjustment for BMI. Conclusions Traditional cardiovascular risk factors were not associated with the risk of venous thromboembolism after adjustment for BMI. Hypertension, dyslipidaemia and diabetes may not be risk-factors for venous thromboembolism.

Background Results regarding the association between hormonal exposure and risk of Parkinson's disease (PD) are heterogeneous. Objectives To investigate the association of reproductive life characteristics with PD among postmenopausal women. Methods The PARTAGE case-control included 130 female cases and 255 age-matched female controls. Information on gynecological history was obtained from a standardized questionnaire and PD was validated by neurological examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. Results After adjustment for education level, smoking status, professional exposure to pesticides, and coffee and alcohol drinking, bilateral oophorectomy (OR = 3.55, 95%CI = 1.75-7.20), but neither menopause before age 50 years (OR = 1.24, 95%CI = 0.74-2.09) nor hormone therapy (HT; OR = 1.07, 95%CI = 0.62-1.86), was associated with PD. Conclusion Our findings suggest that bilateral oophorectomy is associated with increased risk of PD. © 2021 International Parkinson and Movement Disorder Society.

To the Editor: In their editorial,1 Gersh and Lavie describe the many ways that estradiol impacts cardiovascular health. In addition, the authors rightly question the findings of the Women’s Health Initiative among menopausal women using hormone therapy. Importantly, they emphasise the need for using the most physiological human-identical transdermal estradiol combined with natural progesterone. However, no information is given on …

International audience; OBJECTIVES: Previous studies have reported controversial findings regarding the association of testosterone with mortality in older men. This heterogeneity might be partially explained by comorbidities and the presence of metabolic syndrome, as well as differential associations according to causes of death.METHODS: We used data from a random subsample of the Three-City study, in which hormone levels were measured in 338 men ≥65 years without metabolic syndrome who were followed-up for 12 years. Vital status was determined for all participants from different sources. We used inverse-probability-weighted Cox regression to estimate the hazard ratios (HRs) of cause-specific mortality and 95% confidence intervals (CIs).RESULTS: Over the follow-up period, 130 men died (30 from cardiovascular disease, 45 from cancer, 55 from other causes). The association of testosterone with mortality showed significant heterogeneity across causes of death (p=0.027 and p=0.022 for total and bioavailable testosterone, respectively). Higher testosterone levels were associated with increased cardiovascular mortality (HR for 1-standard deviation increase, 1.86; 95% CI, 1.28 to 2.71 and 1.50; 95% CI, 1.04 to 2.17 for total and bioavailable testosterone, respectively). By contrast, there were no significant associations of testosterone with mortality from cancer and other causes.CONCLUSIONS: Our data suggest that the association of testosterone with mortality in men without metabolic syndrome might be differential according to the cause of death. These findings may partially explain the heterogeneity across studies on the relationship between testosterone levels and mortality.

CONTEXT: Although endogenous estradiol, generally considered as the female hormone, has been little investigated in men, it could play a role in men's health, mortality in particular. The influence of estrogen receptors (ER) genetic polymorphisms on this relationship has never been studied. DESIGN AND PARTICIPANTS: The Three-City cohort study included (1999-2001) 3650 men >/=65 years who were followed for mortality over 12 years. At baseline, total estradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free estradiol (fE2) was estimated using Vermeulen and Sodergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of estradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: 183 men died over the follow-up (cardiovascular disease (CVD), n=44; cancer, n=57; other causes, n=82). After adjustment, there was a quadratic relationship of all-cause mortality with tE2 and fE2 (p-quadratic=0.04 and 0.05, respectively), with higher mortality for the top and bottom tertiles compared to the middle one. These associations were stronger for CVD mortality (p-quadratic=0.01 and 0.02 for tE2 and fE2, respectively) and disappeared for cancer mortality. There was no evidence of an interaction of estradiol with any ER polymorphisms on all-cause mortality. CONCLUSION: In elderly men, we showed a nonlinear association of tE2 and fE2 with all-cause mortality. These quadratic relationships were stronger for CVD mortality and did not exist for cancer mortality. ER genetic polymorphisms did not modify this association. This article is protected by copyright. All rights reserved.

ObjectiveTo examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies.MethodsWe used data from the French National Health Insurance databases. Patients with incident MND (2010–2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression. Poisson, Gompertz, and multistep models were used to model the relation between age and incidence. We performed a meta-analysis (n = 28 studies) and used meta-regression to examine the relation of age with incidence rates and ratios.ResultsIn France, we identified 10,848 patients with incident MND (6,021 men, 4,827 women). Incidence was higher in men than in women in all age groups. M/F ratios were significantly different across age groups and followed a quadratic trend (p < 0.001). Between 20 and 49 years, the average M/F ratio was 2.26 (95% confidence interval [CI] = 1.96–2.62); it was 1.41 (95% CI = 1.35–1.47) between 50 and 84 years, and 1.88 (95% CI = 1.64–2.17) after 85 years. Incidence was lower in women than men at younger ages, but increased more steeply in women than men. Similar patterns were observed in the meta-analysis of incidence studies, especially in 19 higher-quality studies.ConclusionThe relation between age and M/F incidence ratios of MND follows a quadratic U-shaped pattern with an abrupt drop after the fifth decade. The change in M/F ratios before and after menopause suggests that reproductive/hormonal protective factors have a role in women and should prompt further studies to explore this hypothesis.

Previous studies have shown controversial results about the role of testosterone in all-cause mortality in elderly men. We hypothesized that metabolic syndrome (MetS) could partly explain this discrepancy. We therefore examined the association of all-cause mortality with total and bioavailable testosterone, taking into account the MetS. We used data from the Three-City Cohort (3C) study with 12-year follow-up. The 3C study included 3650 men aged >65 years in three French cities. Hormone was measured in a random subsample of 444 men, and MetS was determined as stated by the International Diabetes Federation criteria. We used inverse-probability–weighted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Of 444 men included in the analysis, 106 (23.9%) had MetS at baseline, and 166 died over the follow-up. There was a significant interaction between testosterone level and MetS for all-cause mortality (P = 0.002 and P = 0.008 for total and bioavailable testosterone, respectively). Among men with MetS, a decrease in one standard deviation of testosterone was associated with higher mortality risk [HR 1.78 (95% CI 1.13 to 2.78) and HR 1.83 (95% CI 1.17 to 2.86) for total and bioavailable testosterone, respectively]. By contrast, there was no association of testosterone with mortality risk among men without MetS. Our results suggest that MetS modifies the association between testosterone and mortality in older men. If confirmed, these findings could contribute to improve risk stratification and better manage the health of older men., We evaluated the association of testosterone with mortality in men and found metabolic syndrome (MetS) was an effect modifier of this relationship. Low testosterone increased mortality among men with MetS.

Background : Use of antidepressants is seen to be a risk factor for type 2 diabetes, even though the underlying mechanisms remain unclear. We examined whether antidepressant use was associated with change in fasting plasma glucose, glycated haemoglobin (HbA1c), β-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) over time. Methods : Participants in the French D.E.S.I.R. cohort study included over 4700 men (48.1%) and women, free of diabetes, aged 30–65 years at baseline in 1994–96 (D.E.S.I.R. 0), who were followed for 9 years at 3-yearly intervals (D.E.S.I.R. 3, 1997–99; 6, 2000–02; 9, 2003–05). Antidepressant use, fasting plasma glucose, HbA1c, HOMA2-%B and HOMA2-%S were assessed concurrently at four medical examinations. Linear mixed models were used to examine the cross-sectional and longitudinal associations of time-dependent antidepressant use with changes in these four biological parameters. Results : Mean fasting plasma glucose and HbA1c increased whereas HOMA2-%B and HOMA2-%S decreased over the follow-up. In a fully adjusted model, there were no differences in: mean fasting plasma glucose ( β = 0.01 mmol/l, P = 0.702); HbA1c ( β = 0.01 %, P = 0.738); HOMA2-%B ( β = 0.00, P = 0.812); or HOMA2-%S ( β =−0.01, P = 0.791) at baseline (1994–96) between antidepressant users and non-users. The interaction term with time also suggested no differences in the annual change in: fasting plasma glucose ( β = 0.00 mmol/l, P = 0.322); HbA1c ( β = 0.00 %, P = 0.496); HOMA2-%B ( β = 0.00, P = 0.609); or HOMA2-%S ( β = 0.00, P = 0.332) between antidepressant users and non-users. Similar associations were observed in analyses of type and cumulative use of antidepressants over follow-up. Conclusion : Our longitudinal data show that use of antidepressants is not associated with altered glucose metabolism, suggesting that the association between antidepressant use and diabetes reported by previous studies may not be causal. Detection bias or clinical ascertainment bias may account for much of this apparent association.

BACKGROUND: The inflammatory biomarker α1-acid glycoprotein (AGP) was found to have the strongest association with 5-year mortality in a recent study of 106 biomarkers. We examined whether AGP is a better biomarker of mortality risk than the more widely used inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP). METHODS: We analyzed data for 6545 men and women aged 45–69 (mean 55.7) years from the Whitehall II cohort study. We assayed AGP, IL-6 and CRP levels from fasting serum samples collected in 1997–1999. Mortality followup was until June 2015. Cox regression analysis was used to model associations of inflammatory biomarkers with all-cause, cardiovascular and cancer-related mortality. RESULTS: Over the mean follow-up of 16.7 years, 736 deaths occurred, of which 181 were from cardiovascular disease and 347 from cancer. In the model adjusted for all covariates (age, sex, socioeconomic status, body mass index, health behaviours and chronic disease), AGP did not predict mortality beyond the first 5 years of follow-up; over this period, IL-6 and CRP had stronger associations with mortality. When we considered all covariates and biomarkers simultaneously, AGP no longer predicted all-cause mortality over the entire follow-up period (adjusted hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90–1.08). Only IL-6 predicted all-cause mortality (adjusted HR 1.22, 95% CI 1.12–1.33) and cancer-related mortality (adjusted HR 1.13, 95% CI 1.00–1.29) over the entire follow-up period, whereas CRP predicted only cardiovascular mortality (adjusted HR 1.30, 95% CI 1.06–1.61). INTERPRETATION: Our findings suggest that AGP is not a better marker of short-or long-term mortality risk than the more commonly used biomarkers IL-6 and CRP.

The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and medications for chronic diseases may offset such benefit.This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community.Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively.The mean age was 73.8 ± 5.3 years, and 36.7% were men. Only 5% of the participants had ≥5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with ≥5 metrics at the ideal level (compared with those with ≤2), there was a 29% (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend 0.001).Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks.

Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migraineurs is magnified by the use of hormonal contraceptives. As migraine prevalence is high in women of reproductive age, it is common to face the issue of migraine and hormonal contraceptive use in clinical practice. In this document, we systematically reviewed data about the association between migraine, ischemic stroke and hormonal contraceptive use. Thereafter a consensus procedure among international experts was done to develop statements to support clinical decision making, in terms of cardiovascular safety, for prescription of hormonal contraceptives to women with migraine. Overall, quality of current evidence regarding the risk of ischemic stroke in migraineurs associated with the use of hormonal contraceptives is low. Available data suggest that combined hormonal contraceptive may further increase the risk of ischemic stroke in those who have migraine, specifically migraine with aura. Thus, our current statements privilege safety and provide several suggestions to try to avoid possible risks. As the quality of available data is poor further research is needed on this topic to increase safe use of hormonal contraceptives in women with migraine.

To assess whether AF is a risk factor for cognitive dysfunction we used prospective data on AF, repeat cognitive scores, and dementia incidence in adults followed over 45 to 85 years.Data are drawn from the Whitehall II study, N = 10 308 at study recruitment in 1985. A battery of cognitive tests was administered four times (1997-2013) to 7428 participants (414 cases of AF), aged 45-69 years in 1997. Compared with AF-free participants, those with longer exposure to AF (5, 10, or 15 years) experienced faster cognitive decline after adjustment for sociodemographic, behavioural, and chronic diseases (P for trend = 0.01). Incident stroke or coronary heart disease individually did not explain the excess cognitive decline; however, this relationship was impacted when considering them together (P for trend 0.09). Analysis of incident dementia (N = 274/9302 without AF; N = 50/912 with AF) showed AF was associated with higher risk of dementia in Cox regression adjusted for sociodemographic factors, health behaviours and chronic diseases [hazard ratio (HR): 1.87; 95% confidence interval (CI): 1.37, 2.55]. Multistate models showed AF to increase risk of dementia in those free of stroke (HR: 1.67; 95% CI: 1.17, 2.38) but not those free of stroke and coronary heart disease (HR: 1.29; 95% CI: 0.74, 2.24) over the follow-up.In adults aged 45-85 years AF is associated with accelerated cognitive decline and higher risk of dementia even at ages when AF incidence is low. At least in part, this was explained by incident cardiovascular disease in patients with AF.

International audience; Scarabin PY, et meta-analysis by Mohammed et al (1) confirms the safety advantage of transdermal vs oral estrogens with respect to the risk of venous thromboembolism (VTE). Surprisingly, the quality of evidence is described as very low (see Table 4 in the report). We believe that this quality rating based on “the observational nature of the studies and inconsistency of results” is not appropriate...

There is increasing evidence of a role of vascular risk factors and disease in decline of physical function. Lifetime estrogen exposure is associated with cardiovascular disease among postmenopausal women. Whether reproductive history is related to motor decline remains poorly investigated. Analyses are based on elderly women from the Three-City Study followed over 10y. We examined the cross-sectional and longitudinal associations of age at menopause, oophorectomy, and parity with gait speed (GS, cm/s) and disability. One-year older age at menopause was associated with faster baseline GS (beta: 0.21; 95% CI: 0.01;0.42) and lower disability hazard over the follow-up (HR=0.98; 95%CI:0.97;0.99). Oophorectomy was associated with slower baseline GS (beta:-5.07; 95%CI:-9.07;-1.07). There was no association of parity with GS and disability. Higher endogenous estrogen exposure during reproductive life may be protective for motor function in the elderly. These results are consistent with the hypothesis of a cardiovascular component of motor function.

The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE.A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy.Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women.Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.

Context: The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. Objective: We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. Methods: Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. Results: Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62–1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. Conclusion: Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.

Introduction Hormone therapy (HT) is the most effective treatment to counteract menopauserelated symptoms. Because venous thromboembolism (VTE) is the main harmful effect of HT among young postmenopausal women, reducing VTE risk appears to be a relevant strategy to improve the benefit/risk profile of HT among postmenopausal women. Methods This article is a review of recent findings regarding the VTE risk among women using HT. Results Recent data confirmed the safety of the transdermal route of estrogens administration in postmenopausal women requiring treatment. In addition, epidemiological data showed that use of concomitant progestins could increase VTE risk compared with progesterone use. Finally, results of a meta-analysis showed that the VTE risk increased with doses of oral estrogens. Conclusion The route of estrogen administration, the type of concomitant progestogens and the dose of estrogens are three important determinants of the thrombotic risk among postmenopausal women using HT.

Venous thromboembolism (VTE) is a main harmful effect of oral estrogen therapy among postmenopausal women. Transdermal estrogens may be safer but early results need to be confirmed. This review provides a summary of the most recent findings regarding the VTE risk among oral versus transdermal estrogens users.Since 2008, we identified five relevant observational studies. Among them, two large cohort studies confirmed that oral but not transdermal estrogens were associated with VTE risk among postmenopausal women. In an updated meta-analysis of current data, pooled risk ratios for VTE were 1.9 [95% confidence interval (CI) 1.3-2.3] and 1.0 (95% CI 0.9-1.1) among oral and transdermal estrogens users, respectively. In addition, one recent cohort study showed that transdermal estrogens did not confer an excess risk of recurrent VTE among postmenopausal women with a history of VTE. The difference in VTE risk between oral and transdermal estrogen users is supported by biological data. Whereas oral estrogens can increase thrombin generation and induce a resistance to activated protein C, transdermal estrogens have minimal effects on hemostatic variables.Transdermal estrogens may improve substantially the benefit/risk ratio of postmenopausal hormone therapy and should be considered as a safer option, especially for women at high risk for VTE.

International audience; To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background. Systematic review and meta-analysis. Medline. Eight observational studies and nine randomised controlled trials. Studies on hormone replacement therapy that reported venous thromboembolism. REVIEW MEASURES: Homogeneity between studies was analysed using chi(2) and I(2) statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model. Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P

Despite a decrease in the use of postmenopausal hormone therapy (HT) over the last decade, many women are still prescribed this treatment, as it remains the most effective means of counteracting climacteric symptoms. Its use declined when it was shown that HT increases the risk of breast cancer, stroke and venous thromboembolism (VTE). Nevertheless, that benefit/risk ratio was established among women using oral estrogens alone or combined with a specific progestogen and it cannot necessarily be extrapolated to other HTs. Oral estrogens increase the risk of VTE especially during the first year of treatment and past users revert to a similar risk as women who have never used them. There is now growing evidence that VTE risk among HT users strongly depends on the route of administration. Indeed, transdermal estrogens, unlike oral estrogens, are not associated with an increased VTE risk and biological data support this difference between oral and transdermal estrogens. In addition, transdermal estrogens may not confer additional risk in women at high risk of VTE. Significant differences in thrombotic risk between HT preparations also relate to the concomitant progestogen. Studies have consistently shown that VTE risk is higher among users of combined estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, two observational studies found that norpregnane derivatives are associated with an increased VTE risk, whereas micronized progesterone may be safe with respect to thrombotic risk. In conclusion, transdermal estrogens alone or combined with micronized progesterone may represent the safest alternative for women who require HT.

Objectifs L’association entre la testosterone et la mortalite chez les hommes reste controversee. De plus, l’influence du syndrome metabolique (SM), par ailleurs associe au risque de deces au cours du vieillissement, est mal connue. Nous examinerons les associations entre la testosterone totale (TT) et la mortalite apres 12 ans de suivi, ainsi que l’influence du SM, chez les hommes de la cohorte des Trois Cites (3C). Methodes L’etude 3C a inclus 3650 hommes âges entre 1999 et 2001 dans trois villes francaises. Le dosage de TT a l’inclusion a ete realise chez 443 sujets ; parmi eux, 166 decedaient apres 12 ans de suivi. Les hazard ratios (HR) du risque de mortalite et leurs intervalles de confiance a 95 % (IC a 95 %) ont ete estimes a l’aide de modeles de Cox. Resultats Apres ajustement sur les facteurs de risque, une relation en J a ete mise en evidence entre la TT et le risque de mortalite (p Conclusions Nos resultats mettent en evidence un lien complexe entre les niveaux de TT et la mortalite chez les hommes. De plus, cette relation semble etre modulee par la presence du SM.

International audience; Postmenopausal hormone therapy (HT), which consists of exogenous estrogens with or without combined progestogens, remains the most effective treatment of climacteric symptoms. Depending on its characteristics, it may nevertheless increase the risk of venous thromboembolism, and its effects on hemostasis have been studied for several decades. The aim of this review was to summarize current knowledge on the effects of HT on hemostasis, taking into account the route of estrogen administration, the daily dose and chemical structure of estrogens, and the pharmacologic class of progestogens. Data from randomized controlled trials that included a control group (either placebo or no treatment) were selected, and analysis was conducted on different generations of biomarkers. Overall, studies showed a hemostasis imbalance among oral estrogen users with a decrease in coagulation inhibitors and an increase in markers of activation coagulation, leading to global enhanced thrombin generation. By contrast, transdermal estrogen use was associated with less change in hemostasis variables and did not activate coagulation and fibrinolysis. No clear difference in HT effects on hemostasis was highlighted between daily doses of estrogens, between estrogen compounds, and between pharmacologic classes of progestogens. Changes in hemostasis are in accordance with clinical results showing an increased thrombotic risk with oral--but not transdermal--estrogen use.

International audience; In older postmenopausal women, high levels of endogenous estrogen have been related to adverse health outcomes including ischemic arterial disease (IAD). Whether estrogen receptor-α (ESR1) and -β (ESR2) polymorphisms modulate the effects of estrogens on IAD has not been investigated. In the Three-City prospective cohort study among subjects older than 65 years, we used a case-cohort design in which plasma levels of total and bioavailable 17β-estradiol were measured. After exclusion of postmenopausal women using hormone therapy, a random subcohort of 533 women and 105 incident cases of first IAD events over 4 years of follow-up were analyzed. Five common polymorphisms of ESR1 and ESR2 were genotyped. Hazard ratios (HRs) of IAD for a 1-SD increase in hormones levels by the genotypes were estimated from Cox models after adjustment for cardiovascular risk factors and a correction for multiple testing. We also investigated the role of hemostasis and inflammation as potential mediators. Neither estrogens nor IAD risk was significantly associated with estrogen receptor polymorphisms. Overall, IAD risk increased with total estradiol [HR1.40, 95% confidence interval (CI) 1.11-1.77]. Stratified analysis by genotypes showed that total estradiol was positively related to IAD risk in women with ESR1 rs9340799-AA genotype but not in women with the AG/GG genotype (HR 1.62, 95% CI 1.22-2.17 and HR 1.03, 95% CI 0.81-1.30, respectively; P for interaction

Synergism between non-O blood group and oral estrogen in the risk of venous thromboembolism among postmenopausal women: The ESTHER Study

Contexte Les estrogenes oraux induisent une hypercoagulabilite mais le lien entre l’estradiol plasmatique et l’hemostase est peu connu. De plus, le role des hormones sexuelles endogenes dans le developpement de l’atherothrombose chez les femmes menopausees est incertain. Objectif Etudier les interrelations entre hormones sexuelles endogenes, hemostase et incidence a 10 ans des evenements cardiovasculaires chez les femmes menopausees. Methodes Les parametres de l’hemostase (fibrinogene, facteur Willebrand, generation de thrombine in vitro, D-Dimeres), l’estradiol, la testosterone et la SHBG plasmatique ont ete mesures dans un echantillon aleatoire de 623 femmes participant a l’etude de cohorte prospective des Trois-Cites (3C), âgees de plus de 65 ans et ne prenant aucun traitement hormonal. Apres 10 annees de suivi, 69 evenements cardiovasculaires majeurs sont survenus. Les hazard ratios (HR ; intervalle de confiance a 95 %) associes a une variation d’un ecart-type de chaque predicteur ont ete estimes par des modeles de Cox multivaries prenant en compte les facteurs de risque cardiovasculaires traditionnels. Resultats Le risque cardiovasculaire augmentait significativement avec l’estradiol (HR = 1,49 ; 1,10–2,02 ; p = 0,01), le fibrinogene (HR = 1,34 ; 1,05–1,70 ; p = 0,02), le facteur Willebrand (HR = 1,56 ; 1,19–1,05 ; p p = 0,02) et n’etait pas modifie par la SHBG. L’impact de l’estradiol sur le risque cardiovasculaire s’expliquait en partie par une augmentation du fibrinogene et de la generation de thrombine. Conclusion Les hormones sexuelles et certains parametres de l’hemostase apparaissent comme des predicteurs a long terme du risque cardiovasculaire chez les femmes menopausees apres 65 ans. Une hypercoagulabilite pourrait jouer un role mediateur dans l’effet de l’estradiol sur l’atherothrombose.